HUMAN ALPHA-1-GLYCOPROTEIN AND ITS INTERACTIONS WITH DRUGS12 †,‡

DRUG METABOLISM REVIEWS, 33(2), 161–235 (2001)

HUMAN ALPHA-1-GLYCOPROTEIN AND ITSINTERACTIONS WITH DRUGS†,‡

Z. H. Israili1,* and P. G. Dayton2

1Department of Medicine, Emory University School of Medicine,GMB, 69 Butler Street, Atlanta, GA 30322

2Deutsch Corporation, Lyme, NH 03768

ABSTRACT

For about half a century, the binding of drugs to plasma albumin, the ‘‘silentreceptor,’’ has been recognized as one of the major determinants of drug ac-tion, distribution, and disposition. In the last decade, the binding of drugs,especially but not exclusively basic entities, to another plasma protein, alpha1-acid glycoprotein (AAG), has increasingly become important in this regard.The present review points out that hundreds of drugs with diverse structuresbind to this glycoprotein. Although plasma concentration of AAG is muchlower than that of albumin, AAG can become the major drug binding macro-molecule in plasma with significant clinical implications. Also, briefly re-viewed are the physiological, pathological, and genetic factors that influencebinding, the role of AAG in drug-drug interactions, especially the displace-ment of drugs and endogenous substances from AAG binding sites, and phar-macokinetic and clinical consequences of such interactions. It can be predictedthat in the fulture, rapid automatic methods to measure binding to albuminand/or AAG will routinely be used in drug development and in clinical prac-tice to predict and/or guide therapy.

† This paper was referred by Dr. M. N. Cayen, Schering-Plough Research Institute, Kenilworth, NJ07033.‡ Dedicated to the memory of Dr. Frederick J. Di Carlo.* Corresponding author. Fax: 404-616-5176; E-mail: [email protected]

161

Copyright 2001 by Marcel Dekker, Inc. www.dekker.com

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162 ISRAILI AND DAYTON

I. INTRODUCTION

The binding of drugs to plasma proteins is often the first controlling step indrug distribution. Binding is an important determinant not only of drug action(both therapeutic and toxic) but also of disposition (1–5). Albumin is the majordrug-binding plasma protein in adult humans, alpha-1 acid glycoprotein (AAG,orosomucoid) is the next important one (4–7), playing an important role in thebinding of steroids (8,9) and many basic and neutral drugs (4–7,10).

Plasma concentration of AAG may change under various physiological andpathological conditions (such as during the acute-phase reaction), resulting in al-teration of the binding of various drugs and other ligands. Changes in drug bindingand, consequently, alteration in the levels of unbound (free) drug (CF ) can havea significant effect on both the pharmacokinetics and pharmacodynamics of a drug(3–5,7,11–13).

The topic of binding of drugs to human AAG has been reviewed previously,although some reviews are limited (4–7,14–17). The present review is a compre-hensive update on the subject, covering biochemical properties of AAG, its physi-ological role and polymorphism of its genes, the factors that determine changes inplasma levels of AAG, and binding data for more than 300 drugs and endogenoussubstances. The latter aspect demonstrates that a large number of drugs bind toAAG and, in some cases, AAG is the main drug-binding protein in human plasma.

The finding that protease inhibitors, the mainstay of life-prolonging drugcombinations used in the treatment of patients with acquired immunodeficiencysyndrome (AIDS), are highly bound to plasma proteins, predominantly to AAG(18–23) created a renewed interest in this field. In vitro studies have shown thatthe antiviral effect of the protease inhibitors was attenuated by the addition ofhuman AAG to the medium (18–20,24,25). Therefore, an increase in plasma AAGlevel under pathological conditions may result in treatment failure in such patients(due to higher binding and the resultant lower concentration of the free drug)unless the dosages of the drugs are adjusted appropriately.

II. ALPHA-1-ACID GLYCOPROTEIN

A. Biochemical Properties of AAG

Alpha-1-acid glycoprotein is a negatively charged acidic glycoprotein[pKa � 2.6; isoelectric point � 2.7 (26)], consisting of 59% protein and 41%carbohydrate (26–28). It contains 11% sialic acid (29,30). The reported molecularweight of AAG is between 38,800 and 48,000 (27,28); the value depends on themethod of isolation (16). The molecular weight of the commercially availableAAG is 44,000–44,100 (such as supplied by Biotechnology, Bethesda, MD, ICNBiochemicals, Irvine, CA, Calbiochem, La Jolla, CA, or Sigma Chemical Co., St.Louis, MO). AAG has been crystallized (31) and the amino acid sequence of itspolypeptide chain (a single strand of 204 amino acid residues with disulfide bonds,

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HUMAN ALPHA-1-GLYCOPROTEIN 163

and secondary and tertiary structures) (26,28,29,32,33) has been determined. Thenature, structure, and spatial organization of the five carbohydrate residues in theAAG molecule has been elucidated (29,32,34,35).

The structure of the genes encoding AAG, located on human chromosome9 (9q31-34.1) (36), has been determined (37). The AAG genes exhibit polymor-phism (36), giving rise to a number of alleles (38,39). The cDNA of AAG has beencloned and its nucleotide sequence determined (33). The amino acid sequence ofAAG and the locations of introns in its structural gene are similar to that of themembers of the protein superfamily (designated as lipocalins), which includesretinol-binding protein, alpha-lactoglobulin, alpha 2µ-globulin, and beta1-micro-globulin (40); sequence similarity has also been found between AAG and epider-mal growth factor receptor (41). Because of the immunological similarity of AAGand the carcinoembryonic antigen (CEA), it has been suggested that CEA maybe a precursor of AAG (42).

Alpha-1-acid glycoprotein is synthesized mainly in the hepatocytes and pa-renchymal cells (30,43–45) and then distributed in body fluids, including plasma,mucus, gastric juice, jejunal fluid, nasal secretion, synovial fluid, cerebrospinalfluid, ascitic fluid, interstitial fluid, wound exudate, pleural and peritoneal effu-sions, and body excretions (urine and feces) (28). About 60% of AAG in the bodyis present in the central compartment and the remainder in a peripheral compart-ment, most likely the extravascular space (28,30). The rate of synthesis of AAGin the body is about 10 mg/kg/day (28). Recently, the synthesis of AAG in humanendothelial cells (46,47) and alveolar type II cell macrophages (47) has beendescribed. Other tissues can also synthesize AAG in response to inflammation(48). AAG is catabolized by the liver (49) and by human monocytic lineage cells(30,50). The half-life of 125I-labeled AAG is approximately 5 days (50–52) andits renal clearance is low (�0.01 mL/min) (53). The synthesis of AAG is stimu-lated, especially during the acute-phase response (52,54–56), by cytokines(57,58), prostaglandin E2 (47), and cyclic adenosine monophosphate (47). Thetranscription of the AAG gene is induced by the inflammatory cytokines, interleu-kin-1 and interleukin-6 (44,59), and glucocorticoids (60) and is regulated by thetranscription factor AAG/enhancer-binding protein beta and NF-κB or Nopp140(61–63).

Several binding sites for AAG have been identified on (human) monocytes,granulocytes, and polymorphonuclear leukocytes (64), which have specific recep-tors for AAG. AAG also binds to specific lectinlike receptors on epithelium of (rat)prostate gland and seminal vesicles (65). The human adrenal cortex has glycogen-specific receptors for AAG (66,67). These receptors are blocked by several steroidhormones (65–67).

Alpha-1-acid glycoprotein is stable under mild heating conditions [55°C for5 h (68,69) and 60°C for 12 h (8,70)] or after prolonged storage at �20°C for atleast 2 years (71). However, an apparent increase in AAG concentration afterstorage of plasma at �20°C for several weeks has also been reported (72). Heatsterilization can lead to denaturation (73), as well as polymerization of AAG (74).

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It is to be acknowledged that Dr. Wickerhauser and colleagues (American RedCross) developed a method for large-scale preparation of crystalline AAG (27),which made it possible for many investigators (including the authors) to carry outdrug-binding studies with purified AAG.

B. Physiological Role of AAG

The precise role of AAG in the body remains unclear. However, it is oneof the major steroid-binding (8,9,30), catecholamine-binding (75,76), and drug-binding and transporting proteins in plasma (5–7,76). In the endothelial cells,AAG is an important component of the capillary barrier, which is essential forcapillary charge selectivity (46). In addition, AAG appears to have many diversefunctions, although a majority of these may be of significance only under patho-logical conditions. For example, AAG may serve as a general protective agent ininfections and against toxins, by binding to toxic lectins (77), endotoxins (78),and bacterial lipopolysaccharide (78), and in providing protection against shock(in rodent models) (78,79). It inhibits the attachment of Mycoplasma pneumoniato human alveolar macrophage (80), and of human immunodeficiency virus type1 (HIV-1) envelope glycoprotein in CD4� monocytic cells (the first step in theHIV-induced depletion of CD4� cells) and macrophages (81). AAG inhibitsrotavirus (SA-II) replication by acting directly on the virus particle (82).

Although AAG stimulates human mononuclear cells and macrophages tosecrete tumor necrosis factor-α (TNF-α) (83), it also inhibits TNF-inducedapoptosis of (mouse) hepatocytes (84) and provides protection against other toxiceffects of TNF (85). AAG appears to have a protective effect against neonatalsepsis (86). In the polymerized form, it inhibits some strains of influenza virus(74), as well as the invasion by malarial parasites (87); the latter observation couldnot be duplicated in another study (88).

Alpha-1-acid glycoprotein possesses nonspecific immunosuppressive activ-ity (89–91). It has been suggested that AAG may be involved in preventing therejection of the fetus (as an allograft) by the mother (92), by way of immunosup-pression. AAG inhibits phagocytosis (93), neutrophil activation (94), and plateletaggregation (95,96). On the other hand, AAG might contribute to the cellularinitiation of coagulation and inflammation by increasing TNF expression and se-cretion in human monocytes (cited earlier) (83). High levels of AAG in plasmahave been associated with gallstone formation (97).

Alpha-1-acid glycoprotein or its precursor may play a role in the maturationand activation of T- and B- lymphocytes (98), especially in the T3–T i antigen-specific pathway of T-cell activation (99). The interaction of AAG with collagenleads to the formation of long fibers (100) which may have a role in wound heal-ing. The glycoprotein may also control cell differentiation and spatial position inthe human adrenal cortex, which has glycoform-specific receptors for AAG (67).

The significance of some of the actions of AAG is not clear. For example,

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AAG interacts with phospholipids and influences permeability of membranes toerythrocytes (101) and AAG-containing liposomes serve as vehicles for water andion transport across lipid membranes (102). It acts as a cofactor in the lipoproteinlipase reaction (103). AAG also has a growth-promoting effect on HeLa, H-6,and nerve cells (104,105). It may also act as a nonfunctional receptor for alpha1-adrenergic receptor antagonists (106). AAG increases the number of beta-adrener-gic receptors on human mononuclear leukocytes (107).

Although AAG is one of the acute-phase proteins, the reason(s) why plasmalevels of AAG increase in response to inflammation or tissue injury (Table 2) arenot well understood. However, the increased synthesis and secretion of AAG maybe the response of the tissue to proinflammatory stimuli, as supported by the fol-lowing biological actions of AAG: (1) immunosuppressive action (89,90), (2) im-munemodulation activity (91), (3) inhibitory effect on interleukin-2 secretion bylymphocytes (90), (4) inhibition of lymphocyte proliferation (89,90), (5) bindingof both exogenous and endogenous inflammatory mediators, including histamine(78,108,109), (6) inhibition of platelet aggregation (95), (7) inhibition of neutro-phil activation (94), and (8) induction of the synthesis of interleukin-1 receptorantagonist (110). It is of note that in some patients, the acute-phase reaction inresponse to tissue injury (surgery) is either incomplete or absent and plasma AAGlevels do not rise (111).

III. FACTORS WHICH DETERMINE DRUG BINDING TO AAG

The in vivo binding of drugs to AAG is influenced by a number of factors,including (1) the concentration of the ligand, (2) concentration of AAG, (3) pH,(4) presence of other ligands which compete with binding to AAG, (5) presenceof other proteins (such as albumin) which also bind the ligand, (6) allosteric co-operativity between the proteins (e.g., between albumin and AAG) (112–117),(7) the number and the nature of the binding sites on AAG, (8) ethnicity of theprotein donor (72), and (9) the relative abundance of the AAG variants. Factorsthat alter the plasma (serum) concentration of AAG or change in its structure orhave influence on the nature of the binding sites can have significant effect onthe in vivo binding, which, in turn, would influence the pharmacokinetics andpharmacodynamics of drugs (1–4,10–13).

A. Genetic Polymorphism of AAG Genes; Phenotypes and Variantsof AAG

Long before the genes for AAG were detected, polymorphism in its gene(s)was recognized with the observation of heterogeneity in the molecule and isolationof a number of polymorphs and variants of human AAG (38,118–122). The hetero-geneity in both the protein and the carbohydrate portions of the AAG molecule

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(123,124) is due to the position of the attachment of sialic acid in the AAG mole-cule (122), abnormal glycosylation (125), or genetic polymorphism (see next para-graph). The apparent heterogeneity may also be because of an artifact of the isola-tion process (126).

The AAG molecule is encoded by two genes, at closely linked loci, ORM1and ORM2 (39), mapped to chromosome 9 (9q31-34.1) (36); two additional (tan-dem) genes, AGP1 and AGP2, have also been detected (39). Polymorphism inthe genes for AAG gives rise to a number of alleles, such as ORM1 *F1, ORM1*F2, ORM *S, ORM1 *F2, ORM1 *F2S, ORM1 *F5, ORM*2.1, ORM2 A, F1/A (ORM 1/A), and ORM 2/A (39,127–129). Ethnic differences in allele frequen-cies, usually determined by isoelectric focusing and immunoblotting, have beennoted in different populations (127,128,130–133). The AAG gene products ofORM1 and ORM2 give rise to the main phenotypes, variants A (ORM2 A), F1(ORM1 F1), and S (ORM1 S), as encoded by the two genes (127,134). Interindi-vidual variability has been found in the relative proportion of the variants derivedfrom the two genes of AAG (ORM1 � ORM2) (133,134), but no gender-relateddifferences have been detected (133). Inheritance of the variants of AAG has beenreported (135).

B. Effect of Aging, Gender, Pregnancy, Hormones, and Disease onthe Structure and Binding Sites of AAG

The binding of drugs may be altered in certain pathological and physiologicalstates, due to abnormal AAG as a result of (1) alteration in sialylation and fucosyl-ation (7,136,137), (2) changes in glycosylation pattern (137), (3) increasedbranching of oligosaccharide chains (137), or (4) reduced number of binding sitesper molecule of AAG (138). Changes in the glycosylation pattern of AAG havebeen demonstrated in healthy elderly individuals (139), in women receiving oralestrogens (140,141), or in the late stage of pregnancy (140). AAG from femaleswas found to have more highly sialylated glycoforms compared to that from males(142). The drug-binding capacity decreases with increasing branching of the gly-can chain (142).

Abnormal AAG has been noted in patients with (1) cancer of the breast,colon, liver, lung, prostate, and stomach and malignant mesothelioma (55,91,143–148), (2) diabetes (136), (3) major depression (149–151), (4) liver disease(137,145), (5) renal insufficiency (138), (6) infection (152), (7) septic shock (153),(8) Still’s disease (in adults but not in children) (154), (9) systemic lupus erythe-matosus (52,57), (10) inflammatory diseases (54,55,123,141,155–157), and (11)posttransplantation (158). Plasma from mentally retarded Caucasian patients(120) and normal adults under conditions of severe stress (121) had the sameproportion of AAG variants as healthy Caucasian adults, but different from thatin healthy Japanese adults (119). The relative concentrations of variants of AAGare different under acute-phase conditions as compared to that in normals (157).

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Any change in the structure or binding capacity of AAG may alter the bindingand, thus, the pharmacokinetics and pharmacodynamics of highly bound drugs.

C. Plasma (Serum) Levels of AAG

1. Plasma (Serum) Levels of AAG in Normal Subjects

Plasma or serum AAG levels in healthy young adults have been reported tobe in the range of 55–140 mg/dL (12–31 µM) (16,28,158–161). The techniquesemployed to measure AAG include rocket or affinity immunoelectrophoresis,concanavalin A crossed immunoaffinoelectrophoresis, sodium dodecyl sulfatepolyacrylamide gel electrophoresis (SDS–PAGE), capillary-zone (or gel) electro-phoresis, the Biuret method, radial immunodiffusion assay, the electroimmunodif-fusion method, immunoturbidimetric assay, laser nephelometry, laser immuno-nephelometry, high-performance liquid chromatography, fast protein liquidchromatography, chromatography on immobilized metal chelate affinity absor-bent, radioimmunoassay, heterosandwich immunoassay, solid-phase enzyme-linked immunoadsorbent assay (ELISA) with electrochemical detection, or a fluo-rimetric method using auramine-O complexation). A diurnal variation (up to49%) in plasma AAG levels has been observed (16,162); however, it appearsto be absent in the elderly (163). Gender-related difference in plasma levels ofAAG (higher in men than in women) has been reported in some (159,164) butnot in all studies (134,165,166) (Table 1). Ethnic differences have been reportedin plasma AAG levels: Chinese � Caucasians (72,166); Iranians � Irish (167);African-Americans � Caucasians (131,168); Chinese males � Japanese males(169).

The concentration of AAG in the plasma of 18–20-week-old fetuses is quitelow (3.1–5.9 mg/dL). The levels increase with age in premature infants: about 9mg/dL at 30 weeks (170), 10 mg/dL at 30–36 weeks of gestation (170), and 12–34 mg/dL in the full-term neonate (12,86,165,170–178). AAG levels rise rapidlyafter birth to about 40–52 mg/dL at 1 month of age (170,179,180) and then in-crease linearly up to the age of 1 year (181). The levels of AAG in children, 1year of age and above, are the same as in adults (170,182). Values of 9–40 mg/dL of AAG have been reported in cord serum (28,165,172,183,184).

2. Nonpathological Factors Which Modify Plasma (Serum) AAG Levels

Plasma AAG levels have been reported to be higher (159,185–190), lower(191), or the same (139,192) in healthy elderly compared to the young individuals(Table 1). Some of the reasons for the variability in the results of the studies maybe the presence of mild infection, inflammation, or obesity in some individuals,differences in nutritional status or extracellular volume, or the small number ofstudy subjects.

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Table 1. Nonpathological Factors Which Influence Plasma AAG Levels

Factor Changea Ref.

Agingb Higher 159, 185–190NCc 139, 192Lower 191

GenderMaled Higher 159, 164Maled No difference 134, 165, 166Female

Menstrual cycle (middle) Higher 193Pregnancy Lower 177, 178, 195–197

NC 165, 171, 198, 222Parturient state Lower 176, 199

NC 172Puerperium state Higher 177, 196Postmenopausal state Higher 164, 194

Strenuous exercise NC 200Smoking NC 201

Higher 202Secondary smoke Higher 203, 204

Vaccination (diphtheria–tetanus– Higher 45poliomyelitis–typhoid

a Versus normal value.b Elderly versus young.c NC � no change.d Males versus females.

Higher plasma levels of AAG are found in women in the middle of theirmenstrual cycle than at the beginning (193) (Table 1). Postmenopausal womenhave higher AAG levels compared to the younger women (164,194). Plasma AAGlevels have been reported to be low (40–70 mg/dL) in pregnancy, especially in thethird trimester (140,173,177,178,195–197); however, some investigators found nosignificant difference in the levels between pregnant and nonpregnant females(165,171,198) (Table 1). Plasma volume expansion with the resulting dilution ofAAG levels in pregnancy may explain the apparent lower values observed. PlasmaAAG levels may or may not be lower in the parturient than in nonpregnant women(199); mothers during puerperium have higher levels of AAG (177,196) (Table 1).Again, the difference in the results may be due to heterogeneity of populationand health status of the individuals (see above paragraph).

A correlation was observed between serum AAG levels and weight (r �0.62; p � 0.05) in healthy subjects (188); moderately or morbidly obese individu-als have elevated levels of AAG (Table 2). Strenuous exercise in normal subjectshas no effect on plasma levels of AAG (200). Some investigators found no differ-ence in plasma AAG levels of smokers and nonsmokers (201), whereas othersobserved higher levels in smokers (202). Plasma AAG levels were also higher in

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newborn infants of mothers who smoked during pregnancy (203) and in schoolchildren exposed to secondary smoke, compared to those with no exposure totobacco smoke (204).

3. Effect of Disease on Plasma AAG Levels

Plasma levels of AAG increase in various disease states (acute illness, infec-tion, various types of cancer, cardiovascular disease, central nervous system disor-ders, diseases of the kidney, liver, and lung, chronic inflammatory diseases, etc.)(Table 2). AAG levels are higher in obese individuals and in patients with injury,trauma, and severe burns and in recipients of bone marrow and organ transplants(Table 2). In most cases, plasma AAG levels rise as a result of increased AAGsynthesis which is stimulated by the inflammatory cytokines (44,59). Elderly pa-tients with acute illness or with cachexia of chronic disease also have elevatedAAG levels. The levels of AAG rise after surgery, peaking at 3–4 days postopera-tively (179,205,206), and then decline to baseline values after 2–4 weeks (206).In some surgical patients, the acute-phase response is either incomplete or ab-sent (111).

Lower than normal levels of AAG in plasma have been found in patientswith pancreatic cancer, hepatic cirrhosis, hepatitis, hyperthyroidism, nephroticsyndrome, malnutrition, and cachexia (Table 2). Defective acute-phase responsehas also been observed in systemic lupus erythematosus, mixed connective tissuedisease, and systemic sclerosis (Table 2). The plasma AAG level is not influencedby diabetes mellitus type II, congenital heart disease in children, and heart failurein adults (Table 2).

Treatment of disorders in which AAG levels are elevated, such as athero-sclerosis (207), Crohn’s disease (208), inflammatory bowel disease (209), acutemalaria (210), psychiatric disorders (150,151,211), rheumatoid arthritis (212),and some types of cancer (see Table 2), results in a decrease in AAG levels.It has been suggested that plasma level of AAG may be used for detectingmalignancy (213–215), staging of cancer (216), as an indicator of cancer dis-semination (217,218), and prognosis (217,219), as well as a marker of thera-peutic response during chemotherapy and radiation therapy of cancer(144,205,215,219,220,221).

4. Effect of Drugs, Including Hormones, on AAG Levels

The plasma AAG level is altered by treatment with several drugs. In general,the steroid hormones lower plasma AAG levels. The administration of estrogensto normal subjects decreases plasma AAG concentration (141). It has been re-ported that plasma AAG in women on oral contraceptives are significantly lowerthan in control women (or men) (222–225). On the other hand, some investigators

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Table 2. Pathological Conditions Which Modify Plasma AAG Levels

Pathological condition Changea Ref.

Acute Illness (elderly) Higher 189, 358Intensive care patients Higher 5

Cancer (Breast, colon, esophagus, kidney, leuke- Higher 3, 26, 55, 90, 144, 145, 148,mia, liver, lung, larynx, ovary, pancreas, 189, 205, 213, 214, 216–prostate, rectum, stomach, urinary tract, 221, 284, 328, 341, 342,urothelial, uterus) 360–364

Brain (gliomas) Higher 365Pancreas Lower 215

Cardiovascular DiseasesAcute myocardial infarction Higher 3, 5, 189, 334, 343, 366–

369Acute ventricular arrhythmia Higher 370Angina pectoris (stable) Higher 371Atherosclerosis (coronary) Higher 207Coronary artery disease NC 372Chest pain Higher 368

NC 373Congenital heart disease (in children) NC 374Heart failure Higher 375

Central Nervous System DisordersPsychiatric disorders (anorexia nervosa, bu- Higher 150, 151, 211, 376–381

limia, eating disorder, major depression,disruptive behavior, mania, melancholia,schizophrenia)

Depressive illness NC 382Cerebral ischemia/stroke Higher 383Epilepsy Higher 228, 232, 384

InfectionsBacterial (acute) Higher 26, 152, 174, 189, 385, 386Human immunodeficiency virus (HIV)/AIDS Higher 22, 387Malaria (acute) Higher 210, 294, 388–390Meningitis (bacterial) Higher 391Septicemia Higher 140Septic shock Higher 153

Inflammatory DiseasesAnkylosing spondylitis Higher 54Inflammatory bowel disease Higher 209, 392Chronic ulcerative colitis Higher 393Crohn’s disease Higher 3, 7, 208, 326, 327, 393Pancreatitis (acute) Higher 140Rheumatoid arthritis Higher 3, 5, 26, 52, 55, 140, 155–

157, 161, 212, 311, 327,328, 394–396

Systemic lupus erythematosus Higher 394

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Table 2. Continued

Pathological condition Changea Ref.

InjuryBurns (severe) Higher 3, 397, 398Surgery Higher 140, 179, 180, 205, 206,

343, 399Trauma (chemical and physical) Higher 26, 349

Transplantation (bone marrow, kidney, liver) Higher 158, 400–402Kidney Disease

Renal isufficiency Higher 12, 138, 140, 175, 327, 347,403, 404

Chronic renal failure Higher 5, 53, 345, 395, 405, 406End-stage renal disease Higher 5, 12, 190Nephrotic syndrome NC 327Pyelonephritis Higher 140Renal dialysis patients Higher 12, 407Renal transplant recipients Higher 400, 402Uremia Lower 408Uremia � dialysis Higher 403, 409

Liver DiseasesHepatic insufficiency Lower 12, 175, 410, 411Cholecystitis (acute) Higher 56Cirrhosis Lower 5, 12, 25, 405, 412, 413

NC 327, 347, 355, 395Hepatitis Lower 140

Lung DiseasesInflammation of lungs Higher 145, 189High-altitude pulmonary edema Higher 414

Weight Change (significant)Cachexia Lower 205Obesity (moderate–morbid) Higher 188, 415

Miscellaneous PathologiesAlcoholism NC 355Chronic alcoholism Higher 416, 417Chronic pain Higher 418Diabetes mellitus type I (IDDM) NC 419Diabetes mellitus type II (NIDDM) with or Higher 419, 420

without syndrome XDown’s syndrome Higher 421Hyperthyroidism Lower 422Hypoalbuminemia Lower 311Sickle cell disease Higher 58

Systemic sclerosis/scleroderma Lower 423

a Change from normal values. NC � no change.

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found no significant difference between plasma levels of AAG in young womenon or off oral contraceptives (160). Treatment of women with tamoxifen (withestrogenlike activity) (226) or mifepristone (an antiprogestin drug) (227) also de-creases plasma AAG levels. Estrogen replacement therapy in postmenopausalwomen with elevated AAG levels (164) restores plasma AAG concentration topremenopausal levels (194).

The administration of antiepileptic drugs alters plasma AAG levels (228–230). However, conflicting results have been reported for the effect of some ofthese agents on AAG levels. For example, in some studies, treatment with carba-mazepine or phenobarbital increased the plasma levels of AAG (229,230),whereas in others, there was no effect on AAG levels with either phenobarbital(201) or carbamazepine (231). Yet, a combination of carbamazepine plus pheno-barbital decreased plasma levels of AAG (232). The effect of cimetidine adminis-tration on AAG levels is also not consistent: in one study in which significantlyelevated levels (p � 0.030) were reported (233), whereas in a later study carriedout by the same authors, there was no increase (234).

Alpha-1-glycoprotein levels rise after administration of glucocorticoid, in-cluding prednisone (60,235), anabolic steroids, danazole (222) and oxymetholone(236), isotretinoin (237), perazine (238), amitriptyline (239), and interleukin-6(59). Some, but not all, drugs that induce cytochrome P450 enzymes increaseAAG levels (229,240).

IV. BINDING OF DRUGS AND ENDOGENOUS LIGANDS TOAAG

A. Binding Sites on AAG

1. Number of Binding Sites on AAG Molecule

Although early work on the binding site(s) on the AAG molecule indicatedthe presence of only one important site with high affinity and low capacity(185,241–245), it now appears that there are seven binding sites with varyingaffinities and capacities. All basic drugs bind to one common site on AAG (242–248); the acidic drugs also interact with the same binding site (249). Studies usingfluorescent probes showed that basic drugs not only displaced basic probes butalso acidic probes (68,250), whereas acidic drugs displaced acidic probes but notthe majority of basic probes (251). These studies suggest that the AAG moleculehas one wide and flexible drug-binding area where both acidic and basic drugsbind at locations which significantly overlap and influence each other (251). Morerecent investigations indicate the presence of two separate drug-binding sites onAAG, one with high affinity and the other with low affinity for binding of drugsand steroids, with different specificity and localization of interaction (129,134).In addition, five other binding sites, mostly with low affinity, have been identifiedfor binding of endogenous substances (9,75,252) and drugs (14,244,253–255).However, for practical purposes, only one binding site may be considered forclinical relevance.

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2. Nature of AAG Binding Sites and Binding Interactions with Drugs

The location of the main binding site on the AAG molecule and the aminoacid residues involved in binding have been studied by several investigators (254–256). The topography of the AAG molecule (257) and that of the binding siteson AAG has been determined for some drugs (e.g., antihistamines) (17).

Relationships between the physicochemical properties of ligands with affin-ity for binding to AAG have been investigated for a number of drug classes. Forsome drugs, the binding is related to lipid solubility: Correlations have been foundbetween partition coefficients and the binding of benzodiazepines (246), phenothi-azine neuroleptics (247), and some beta-blockers (258). The binding to AAG isrelated to the hydrophobicity of the anthracycline derivatives (259), antihistamines(260), benzodiazepines (246), and phenothiazines (247). It appears that the bind-ing interactions with AAG of the antidepressants (255), alpha-1 adrenergic recep-tor antagonists (255), some beta-blockers (258), and analgesics (261) are alsohydrophobic in nature. However, for many drugs, such as antiarrhythmics (262),antihistamines (260), beta-blockers (260), benzodiazepines (247), and phenothi-azines, binding does involve both hydrophobic and electrostatic interactions.

3. Role of Genetic Variants of AAG in Binding

The binding affinity of drugs to AAG is also dependent on the relative con-centrations of its genetic variants, which exhibit different specificity for bindingfor a particular drug (188). For example, a specific drug binds to each of the twovariants (A and F1*S; see Sec. III.A) via a single common binding site(129,134,263) but with different affinity. Disopyramide, imipramine, and metha-done bind selectively to the A variant, whereas dipyridamole, quinidine, and mife-pristone bind preferentially to the F1*S variant; progesterone, propranolol, andchlorpromazine show no selectivity in binding (129,188,263–266); the highestunbound fraction of quinidine was found with ORM1 S (130). Herve et al. (134)were able to generate a three-dimensional quantitative structure–activity relation-ship model for binding of drugs to variant A, but not to variant F1*S. Differencesin binding to these variants may have important pharmacokinetic and clinical im-plications. It is not known if the reported ethnic differences in the binding ofseveral drugs (72) are due to the variability in plasma levels of AAG or relativeconcentrations of its variants.

B. Methods for Determining Binding to AAG

1. General

The usual methods for direct measurement of binding of drugs to solutionsof purified AAG include equilibrium dialysis and ultrafiltration. However, othertechniques have been used, which include capillary-zone electrophoresis (267),

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high-performance capillary electrophoresis/frontal analysis (268), affinity capil-lary electrophoresis (269), isotachophoresis (270), high-performance frontal anal-ysis (271,272), high-performance liquid chromatography (273), sequestrationelectrochemistry (274), circular dichroism (246,247,275), electron spin resonancespectroscopy (276), surface plasmon technology (277), blood dilution method(278), and isothermal calorimetry (279). A rapid automated procedure for de-termining protein binding of a large number of ligands (560 assays in 20 h) hasrecently been described (280).

To measure binding by equilibrium dialysis or ultrafiltration, a knownamount of a drug is added to a solution of pure AAG (at a known concentration)in a buffer and allowed to equilibrate. The free drug is separated from the bounddrug by dialysis or ultrafiltration, and the concentrations of the free (unbound)drug (CF) and the bound drug (CB) are measured. Percent binding (%B) of the drugis calculated from the equation (CT � CF ) � 100/CT, where CT is the total drugconcentration (CB plus CF ). Correlations (positive or negative) between fractionbound (FB), fraction free (FF ), or the ratio of FB/FF with AAG concentration aredetermined by measurement of binding of the drug at different concentrations ofAAG. The equilibrium binding (affinity) constant, KA, is calculated from the equa-tion CB � (BCAP KACF )/(1 � KACF ), assuming one binding site, where BCAP is theapparent capacity of the binding site.

In our opinion, binding studies should be carried out under physiologicalconditions (37°C, pH 7.4) to obtain clinically relevant binding data. The calculatedparameters for binding of a drug to AAG may vary depending on (1) the experi-mental conditions (temperature, time for equilibration, etc.), (2) the source of AAGused (16,281), and (3) the method of interpretation of the binding data (282,283).Commercial AAG may yield different binding data due to heterogeneity of AAGin the different preparations (117).

An indirect method has also been used to determine the relationship of FB

or FB/FF ratio of drugs by measuring the FB and FF of drugs using plasma or sera(from patients or healthy subjects) containing various amounts of endogenousAAG or adding known amounts of purified AAG to whole plasma or AAG-defi-cient plasma [obtained by immunoprecipitation of AAG by rabbit anti-humanAAG globulin (283)]. The indirect method may give incorrect values due to theinterference by albumin and other endogenous substances such as lipids or lipo-proteins present in plasma or serum (75,113,249,253,283–285).

2. Precautions to Be Taken in Binding Studies

A number of precautions should be taken to ensure the reliability of bindingresults (281). Several materials such as plasticizers [e.g., tris-(2-butoxyethyl)-phosphate and di-(ethylhexyl)-phthalate] present in the plastic stoppers of certainblood collection tubes and in plastic transfusion bags may leach into the blood.These plasticizers have been shown to displace drugs from AAG-binding sites;thus, their presence in blood can result in apparently lower binding values

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(15,249,283,286–289). Contamination with heavy metals, even at low concentra-tions (e.g., 50 µM of mercuric ions), may reduce binding of some drugs (290). Theamount of lipids in the dialysis medium can also influence binding to AAG (284).

Because of the health hazard posed by transmission of diseases, such asAIDS, hepatitis, and so forth, by blood products, studies have been carried outto determine if heat treatment (which deactivates HIV) of plasma or AAG solu-tions could be used for binding studies. As mentioned earlier (Sec. II.A), AAGis stable to mild heating conditions (68–70) and the binding of selected drugs isnot altered (8,68,69). However, adequate precautions should be taken in handlingany blood products.

C. Binding of Specific Drugs and Endogenous Ligands to AAG

1. General

Dipyridamole, an inhibitor of platelet aggregation, was the first nonsteroidaldrug found to be bound to AAG (291). Since then, binding parameters of a rapidlyincreasing number of drugs have been determined. The largest category of drugswhich bind extensively to AAG is that used in psychiatry (see Table 3).

For many drugs, particularly bases, the binding to AAG is much more pro-nounced than to albumin (Table 3). For example, the AAG/albumin binding affin-ity ratio for dipyridamole is about 11 (291), 16 for prazosin (285,292), 18 forquinidine (293), 20 for arteether (294), and 1000 for thioridazine (289).

A number of alpha-adrenergic receptor blocking drugs and beta-blockers(alprenolol, carvedilol, oxprenolol, penbutolol, pindolol, propranolol, tertatolol,and timolol) bind avidly to AAG (see Table 3). The analgesics (alfentanil, fen-tanyl, lofentanil, and sufentanil) and the local anesthetics (bupivacaine, etidocaine,lidocaine, and mepivacaine) have high binding affinity to AAG (Table 3). For themajority of the psychoactive drugs, AAG is the main binding protein in plasma(Table 3). Similarly, the cinchona alkaloids quinine and quinidine as well as theantimalarials arteether and artemether bind preferentially to AAG (Table 3).

Other drugs for which AAG is the major binding plasma protein includeacenocoumarol, acridine-4-carboxamide, ajmaline, amitriptyline, apazone, aprin-dine, bepridil, binedaline, betamethasone, chlorpromazine, ciclazindol, clinda-mycin, cocaine, desipramine, diphenhydramine, dipyridamole, disopyramide, do-cetaxel, doxepin, erythromycin, felodipine, fluphenazine, imipramine, lerisetrone,loxapine, melatonin, meperidine, methadone, methoxypromazine, mianserin, mi-befradil, mifepristone (RU486), moxaprindine, nicardipine, nicergoline, nifedi-pine, norgesterol, nortriptyline, olanzepine, opromazine, perazine, perphenazine,phencyclidine, pirmenol, primaquine, prochlorperazine, progesterone, promazine,propafenone, propisomide, reboxetine, remoxipride, rifampicin, ritonavir, semoti-adil, spironolactone, thalidomide, thioridazine, thiothixene, timegadine, triazolam,trifluperazine, triflupromazine, verapamil, the vinca alkaloids, vinblastine andS12363, and zimelidine (Table 3).

The relative significance of binding of drugs to AAG is indicated by the

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Tab

le3.

Bin

ding

ofD

rugs

and

Low

-Mol

ecul

arW

eigh

tE

ndog

enou

sSu

bsta

nces

toH

uman

Alp

ha1-

Aci

dG

lyco

prot

ein

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

KA(M

�1)

orK

D�

(M)

A80

987

(P-I

)�

90%

20A

ceno

coum

arol

(A-C

g)85

%[9

0]K

A�

2.0

�10

524

9E

nant

iom

ers:

%B

:S

�R

302

Acl

arub

icin

(A-C

n)37

%[2

25]

nKA

�1.

2�

104

259

Acr

idin

e-4-

carb

oxam

ide

(A-C

n)76

%[7

5];

FF

�iC

AA

GK

A�

7.8

�10

442

4A

jmal

ine

(A-H

T,

A-A

r)%

B�

high

425

Alc

uron

ium

(Q,

M-R

ix)

35%

[100

]42

6A

lfen

tani

l(A

g,A

n)%

B�

CA

AG:

r�

0.80

398

92%

[63]

;86

–95%

[50

–200

];%

B�

CA

AG

261

[B]/

[F]

�C

AA

G:

r�

0.90

;p

�0.

001

427

Alm

itrin

e(R

-St)

�40

%[5

10]

297

Alp

idem

(A-A

x)97

%[7

5]17

5A

lpre

nolo

l(B

B,

A-H

T)

[B]/

[F]

�C

AA

Gd:

r�

0.72

nKA

�2.

1�

105

685

%[7

0];

FF

�iC

AA

Gd:

r�

�0.

75;

p�

0.00

16

76%

[67]

15[B

]/[F

]�

CA

AG

d:

r�

0.72

nKA

�3.

0�

105

177

%B

�C

AA

G:

p�

0.00

517

7F

F�

iCA

AG

327

55%

[66]

;F

F�

iCA

AG:

r�

�0.

90;

p�

0.00

139

6A

min

oglu

teth

imid

e(A

g)25

%42

8A

min

opyr

ine

(Ag,

A-P

r)�

10%

[40]

KA

�7.

4�

104

L/M

429

Am

itrip

tylin

e(T

C,

A-D

p)K

A�

105

14[B

]/[F

]�

CA

AG

d:

r�

0.73

nKA

�8.

6�

105

149

83%

[70]

KA

�3.

4�

105

253

KA

�4.

0�

105

350

67%

[102

];F

F�

noiC

AA

G43

0M

etab

olite

:N

-Dem

ethy

lam

itrip

tylin

e(s

eeN

ortr

ipty

line)

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Am

pren

avir

(P-I

)90

%25

Am

sacr

ine

(A-C

n)40

%43

1A

nthr

acyc

lines

(A-C

n)31

–61%

259

Apa

zone

(Ag,

A-I

nf)

60%

[115

];[B

]/[F

]�

CA

AG

d:

r�

0.51

;p

�0.

02K

A�

4.1

�10

528

4A

prin

dine

(AIn

f)78

%[6

7];

FF

�iC

AA

GK

A�

4.2

�10

539

5A

rtee

ther

(AM

I)61

%K

A�

2.3

�10

529

448

–62%

432

Art

emet

her

(A-M

I)K

A�

3.2

�10

543

348

–62%

432

Ate

nolo

l(B

B,

A-H

T)

�5%

396

Ate

vird

ine

(A-V

r)47

%[1

00]

434

Met

aboi

lte:

41%

[100

]43

4A

trop

ine

38%

[90]

435

Ben

oxap

rofe

n(N

SAID

)10

%[9

0]24

9B

epri

dil

(CC

B,

A-H

T)

�99

%40

7B

etam

etha

sone

(GC

)43

6B

etha

nidi

ne(A

-HT

)6%

187

Bin

edal

ine

(A-D

p)96

%K

A�

2.2

�10

633

0B

orna

prol

ol(B

B)

60%

[39]

nKA

�8.

4�

105

359

Bro

maz

epam

(BD

Z,

mT

r)K

A�

0.2

�10

524

6B

upiv

acai

ne(L

An)

31%

[20]

,86

%[6

0];

[B]/

[F]

�C

AA

G17

2F

F�

iCA

AG

dK

A�

5.4

�10

519

5E

nant

iom

ers:

R(�

)is

omer

KD

�1.

1�

10�

330

3S(

�)

isom

erK

D�

1.5

�10

�3

303

Bus

piro

ne(A

-Ax)

15–3

0%[7

5]K

A�

2.1

�10

543

8C

anre

none

(Diu

r)�

5%[1

80]

KA

�0.

5�

104

439

(met

abol

iteof

spir

onol

acto

ne)

Cap

saic

in(N

CA

)41

%44

0K

A�

10.5

�10

644

1

(con

tinu

ed)

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Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

Car

bam

azep

ine

(A-C

v)[B

]/[F

]�

CA

AG

d:

r�

0.42

nKA

�2.

5�

104

384

FF

�iC

AA

G:

r�

�0.

3838

410

%[5

0],

34%

[100

],29

%[1

50]

KA

�1.

7�

104

442

KA

�7.

1�

107

L/M

443

Met

abol

ite:

Car

bam

azep

ine-

epox

ide

(A-C

v)5–

15%

,F

F�

iCA

AG:

r�

�0.

5838

4[B

]/[F

]�

CA

AG

d:

r�

0.54

nKA

�1.

6�

104

384

0%44

2K

A�

1.6

�10

7L

/M44

3C

arve

dilo

l(B

B,

A-H

T)

Ena

ntio

mer

s:R

S-ra

cem

ate

KA

�3.

0�

106

273

R-i

som

erK

A�

4.9

�10

627

3S-

isom

erK

A�

2.1

�10

627

3C

efot

iam

(AB

)0%

444

Cef

tria

xone

(AB

)�

5%[2

00]

399

CG

P45

715A

(see

Iral

ukas

t)C

hlor

oqui

ne(A

-MI)

16%

445

Ena

ntio

mer

s:(�

)ra

cem

ate

39%

304

(�)

isom

er35

%30

4(�

)is

omer

48%

304

Met

abol

ite:

Des

ethy

l-ch

loro

quin

e39

%30

4C

hlor

phen

iram

ine

(A-H

1)

Ena

ntio

mer

s:R

(�)

isom

er5%

305

S(�

)is

omer

23%

305

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HUMAN ALPHA-1-GLYCOPROTEIN 179C

hlor

prom

azin

e(P

TZ

,A

-Psy

)F

F�

iCA

AG:

r�

�0.

7818

5F

F�

iCA

AG:

r�

�0.

69;

p�

0.00

132

7[B

]/[F

]�

CA

AG

d:

r�

0.82

nKA

�1.

7�

106

327

KA

�3.

0�

106

243

92%

[80]

KA

�9.

4�

105

244

FF

�iC

AA

G:

r�

�0.

64;

p�

0.00

424

490

%K

A�

3.9

�10

624

7K

A�

3.9

�10

527

4K

D�

2.9

�10

�6

446

KA

�3.

4�

105

446

�90

%44

7C

icla

zind

ol(A

nrct

)75

%44

8C

icle

tani

ne(A

-HT

)K

A�

3.9

�10

429

6C

imox

aton

e(M

AO

I)�

10%

449

Cin

oxac

in(A

B)

�10

%45

0C

ladr

ibin

e(A

-Cn)

�5%

[70]

451

Clin

dam

ycin

(AB

)�

80%

;%

B�

CA

AG

338

KD

�9.

4�

10�

1045

2C

lofib

ric

acid

(LL

D)

�2%

249

Clo

mip

ram

ine

(TC

,A

-Dp)

KA

�7.

2�

105

350

Met

abol

ite:

N-D

emet

hyl-

clom

ipra

min

eK

A�

4.7

�10

535

0C

lona

zepa

m(A

-Cv)

�10

%41

1K

A�

0.3

�10

524

6C

lotia

zepa

m(A

-Ax)

KA

�0.

9�

105

246

Clo

xaci

llin

(AB

)33

%[5

0],

48%

[100

];[B

]/[F

]�

CA

AG:

r2�

0.51

;17

7p

�0.

05C

ocai

ne(L

An)

%B

�C

AA

G:

r2�

0.71

,p

�0.

001

115

%B

AA

G�

%B

HSA

KA

�8

�10

411

5K

A�

2.6

�10

445

3�

99%

;[B

]/[F

]�

CA

AG:

r�

0.89

KA

�2.

5�

104

454

Met

abol

ite:

Coc

aeth

ylen

e[B

]/[F

]�

CA

AG

KA

�5.

2�

104

453

(con

tinu

ed)

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

Cod

eine

(Ag,

A-T

s)�

20%

[50]

455

Con

cana

valin

A(M

sc)

KD

�2

�10

�5

456

Cor

texo

ne(C

St)

KA

�1.

0�

105

252

KA

�2.

0�

105

8C

ortic

oste

rone

(CSt

)K

A�

3.2

�10

425

2K

A�

7.0

�10

48

Cor

tisol

(CSt

)nK

A�

0.15

�10

525

2K

A�

4.0

�10

58

Cyc

lohe

xano

l(M

sc)

22%

[50]

444

DA

-501

8(A

g)%

B�

CA

AG

d45

7D

arod

ipin

e(C

CB

,A

-HT

)90

%K

A�

1.6

�10

545

8D

auno

rubi

cin

(A-C

n)58

%[2

25]

nKA

�2.

8�

104

259

Del

vird

ine

(A-V

r)9%

[100

]45

9M

etab

olite

:N

-Dea

lkyl

-del

vird

ine

(A-V

r)66

%[1

00]

459

Deo

xyco

rtic

oste

rone

(CSt

)K

A�

6.1

�10

527

6D

esm

ethy

lper

azin

e(P

TZ

,A

-Psy

)(s

eePe

razi

ne)

Des

ipra

min

e(T

C,

A-D

p)60

%[8

0]24

4(N

-Dem

ethy

lm

etab

olite

ofim

ipra

min

e)K

A�

1.3

�10

535

0D

iaze

pam

(BD

Z,

A-A

x,M

-Rlx

)K

A�

6.3

�10

414

[B]/

[F]

�C

AA

G:

r�

0.99

;p

�0.

001

165

KA

�2.

5�

105

246

FF

�iC

AA

G;

r�

0.56

,p

�0.

0541

5K

D�

2.8

�10

�6

446

KA

�4.

0�

104

446

19%

[50]

460

Dic

umar

ol(A

-Cg)

60%

447

Dilt

iaze

m(C

CB

,A

-HT

)75

–85%

,%

BA

AG

�2

�%

BH

SA46

1D

iphe

nhyd

ram

ine

(A-H

1)

FF

�iC

AA

G:

r�

�0.

62,

p�

0.01

72

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Dip

heno

xyla

te(A

-Dr)

�20

%[5

0]31

1D

ipyr

idam

ole

(cV

-D,

A-P

t)K

A�

8.0

�10

529

1K

D�

0.8

�10

�5

291

Dis

opyr

amid

e(A

-Ar)

78%

[600

]K

A�

1.0

�10

611

FF

�iC

AA

G:

r�

�0.

54,

p�

0.05

72F

F�

iCA

AG:

r�

�0.

85,

p�

0.01

176

FF

�iC

AA

G37

5[B

]/[F

]�

CA

AG

d:

r�

0.85

nKA

�3.

2�

105

402

[B]/

[F]

�C

AA

G:

r�

0.88

KA

�1.

5�

106

408

43%

[50]

,87

%[2

00]

nKA

�7.

6�

104

462

[B]/

[F]

�C

AA

G:

r�

0.92

;F

F�

iCA

AG;

p�

�0.

9046

280

–90%

463

Ena

ntio

mer

s:R

S(�

)ra

cem

ate

KA

�6.

2�

105

306

R(�

)is

omer

KA

�5.

1�

105

306

KD

�4.

3�

10�

626

6S(

�)

isom

erK

D�

1.5

�10

�6

266

Met

abol

ite:

N-D

ealk

yl-d

isop

yram

ide

38%

[50]

,70

%[2

00];

[B]/

[F]

�C

AA

G:

r�

0.93

462

FF

�iC

AA

G;

r�

�0.

9246

2D

ocet

axel

(A-C

n)%

B�

CA

AG;

FF

�iC

AA

G46

4D

opam

ine

(Adr

)K

D�

1.4

�10

�4

415

Dox

epin

(A-D

p)57

%[6

0];

31–7

2%[3

0–1

20]

466

FF

�iC

AA

G:

r�

�0.

55,

p�

0.05

466

Met

abol

ite:

Ded

oxep

in51

%[6

0];

FF

�iC

AA

G:

r�

�0.

42,

p�

0.05

466

Dox

orub

icin

(A-C

n)32

%[2

25]

nKA

�9.

4�

103

259

Epi

neph

rine

(Adr

)K

D�

1.4

�10

�4

465

(Adr

enal

ine)

Epi

rubi

cin

(A-C

n)31

%[2

25]

nKA

�9.

0�

103

259

Ery

thro

myc

in(A

B)

60–7

0%K

A�

3.5

�10

446

7[B

]/[F

]�

CA

AG

d:

r�

0.94

nKA

�2.

4�

105

412

[B]/

[F]

�C

AA

Gd:

r�

0.88

,p

�0.

0141

3

(con

tinu

ed)

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

Est

radi

ol(S

XH

)K

A�

1.2

�10

58

nKA

�1.

9�

104

252

Est

rone

(SX

H)

KA

�7.

1�

104

8E

stra

mus

tine

(A-C

n)18

%[1

00]

468

Eth

inyl

estr

adio

l(O

C)

57%

469

Etid

ocai

ne(L

An)

93%

[74]

;[B

]/[F

]�

CA

AG:

r�

0.36

,p

�0.

0547

0Fe

lodi

pine

(CC

B,

A-H

T)

86%

471

Feno

fibri

cac

id(L

LD

)�

2%24

9Fe

ntan

il(A

g)44

%[6

3];

25–6

8%[5

0–2

00];

%B

�C

AA

G26

1FK

506

(see

Tac

rolim

us)

Flec

aina

mid

e(A

-Ar)

61%

369

Fluc

onaz

ole

(A-F

n)[B

]/[F

]�

CA

AG

d:

r2�

0.22

4,p

�0.

0534

0%

B�

CA

AG:

r�

0.72

,p

�0.

001

345

Flud

iaze

pam

(BD

Z,

A-A

x)K

A�

1.3

�10

524

6Fl

unitr

azep

am(B

DZ

,Se

d)K

A�

0.3

�10

524

6K

A�

1.2

�10

624

7Fl

uphe

nazi

ne(P

TZ

/A-P

sy)

KD

�3.

9�

10�

644

6K

A�

2.6

�10

544

6Fl

uvas

tatin

(LL

D)

6–67

%47

2Fo

licac

id(V

it)3%

[200

]18

7Fo

sphe

nyto

in(p

A-C

v)13

%47

3Fu

rosa

mid

e(D

iur)

�20

%26

7(F

ruse

mid

e)G

allo

pam

il(C

CB

,A

-HT

)45

%[6

0]K

A�

0.8

�10

535

1E

natio

mer

s:R

-iso

mer

28–4

7%[5

0]30

7S-

isom

er38

–50%

[50]

307

Gem

fibro

zil

(LL

D)

10%

[83]

474

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Hal

ofan

trin

e(A

-MI)

�10

%nK

P�

4.39

L/g

390

Hal

oper

idol

(A-P

sy)

KA

�6.

0�

104

446

KD

�1.

6�

10�

544

6H

eroi

n(A

g)�

20%

[50]

311

Hex

afluo

reni

um(Q

,M

-Rix

)64

%[1

00]

424

Hyd

rala

zine

(V-D

/A-H

T)

36%

187

Hyd

roxy

chlo

roqu

ine

[B]/

[F]

�C

AA

G30

8(A

-Inf

,A

-MI)

Ena

ntio

mer

s:R

-iso

mer

41%

[70]

308

S-is

omer

29%

[70]

308

Imip

ram

ine

(TC

,A

-Dp)

69%

[67]

1592

%[7

0];

FF

�iC

AA

G:

r�

�0.

78;

p�

0.00

16

80%

[100

];91

%[2

50]

368

[B]/

[F]

�C

AA

G:

r�

0.95

,p

�0.

001

nKA

�1.

7�

105

368

FF

�iC

AA

Gd

397

70%

KA

�2.

4�

105

242

69%

[62]

,88

%[1

12]

255

KA

�1.

5�

105

446

KD

�3.

6�

10�

644

6K

A�

1.4

�10

535

0M

etab

olite

:N

-Des

met

hylim

ipra

min

e(s

eede

sipr

amin

e)In

dapa

mid

e(D

iur)

KA

�7.

3�

104

300

%B

�C

AA

G30

1In

dom

etha

cin

(NSA

ID)

KA

�1.

9�

106

1630

%[8

0]16

110

%[9

0]24

960

%[2

00]

KD

�5.

4�

10�

629

5Io

dodo

xoru

bici

n(A

-Cn)

62%

[225

]nK

A�

3.4

�10

425

9Ir

aluk

ast

(A-A

sth)

Bca

p AA

G�

Bca

pH

SA47

5(C

GP

4571

5A)

Irbe

sart

an(A

RB

,A

-HT

)22

%47

6

(con

tinu

ed)

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

Ison

iazi

d(A

B,

A-T

B)

8%[2

00]

295

20%

[100

]47

7M

etab

olite

:A

cety

lison

iazi

d12

%[2

00]

295

Isop

rote

reno

l(B

D)

KD

�1.

0�

10�

475

Isop

rena

line

KD

�1.

4�

10�

446

5Is

radi

pine

(CC

B,

A-H

T)

90%

KA

�5.

1�

105

458

Ena

ntio

mer

s:S(

�)

isom

erK

A�

1.3

�10

631

0R

(�)

isom

erK

A�

1.2

�10

631

0It

anox

one

(NSA

ID)

10%

[90]

249

Itra

cona

zole

(A-F

n)B

�no

CA

AG

345

Ket

amin

e(A

n)10

%[5

0],

21%

[100

]28

6K

etoc

onaz

ole

(A-F

n)�

5%[1

50]

478

KN

I-27

2(P

-I)

�95

%18

98%

23L

eris

etro

n(A

-Sr,

A-E

m)

86%

[225

]K

A�

1.4

�10

536

3L

idoc

aine

(LA

n,A

-Ar)

KD

�1.

5�

10�

511

7(L

igno

cain

e)[B

]/[F

]�

CA

AG:

r�

0.97

,p

�0.

001

nKA

�1.

0�

105

165

FF

�iC

AA

Gd :

r2�

0.63

,p

�0.

001

170

65%

[50]

,80

%[1

50]

367

FF

�iC

AA

Gd :

r�

�0.

93,

p�

0.00

136

7[B

]/[F

]�

CA

AG

d:

r�

0.96

,p

�0.

001

nKA

�1.

0�

105

367

[B]/

[F]

�C

AA

G33

4F

F�

iCA

AG

d :r2

�0.

63,

p�

0.00

137

4F

F�

iCA

AG

d :r

��

0.44

,p

�00

.118

4B

�C

AA

Gd

206

Lig

noca

ine

(see

Lid

ocai

ne)

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Lin

com

ycin

(AB

)K

D�

3.1

�10

�9

452

Lof

enta

nil

(Ag)

87%

[63]

;70

–92%

[50

–200

];%

B�

CA

AG

261

Los

arta

n(A

RB

,A

-HT

)40

%47

9M

etab

olite

EX

P317

4(A

RB

,A

-HT

)24

%47

9L

oxap

ine

(A-A

x)K

D�

4.1

�10

�6

446

KA

�2.

4�

105

446

Lum

efan

trin

e(A

-MI)

�10

%43

3M

apro

tilin

e(A

-Dp)

�10

%,

%B

�no

CA

AG

480

Med

azep

am(B

DZ

,A

-Ax)

B�

sign

ifica

ntK

A�

3.8

�10

524

9M

elat

onin

(Msc

)B

�hi

ghK

A�

2.7

�10

611

6M

eper

idin

e(A

g)4%

[20]

,20

%[6

0]17

3(P

ethi

dine

)[B

]/[F

]�

CA

AG:

r�

0.75

,p

�0.

01nK

A�

0.6

�10

517

3F

F�

iCA

AG

d18

5K

A�

4.0

�10

548

191

%[2

00]

311

FF

�iC

AA

Gd

397

32%

482

37%

[100

],%

B�

CA

AG

483

Met

abol

ite:

1N

orm

eper

idin

e25

%[1

00],

%B

�C

AA

G48

3M

epiv

acai

ne(L

an,

A-A

r)54

%[6

1]K

A�

1.9

�10

532

2M

erca

ptop

urin

e(A

-Cn)

�20

%48

4M

etha

done

(Ag)

[B]/

[F]

�C

AA

Gd:

r�

0.76

nKA

�1.

5�

105

481

80%

[120

]K

A�

4.0

�10

548

172

%[5

0];

83%

[100

];91

%[2

00]

311

[B]/

[F]

�C

AA

Gd:

r�

0.63

,p

�0.

025

nKA

�2.

2�

105

311

Ena

ntio

mer

s:dl

-rac

emat

e[B

]/[F

]�

CA

AG

d:

r�

0.72

,p

�0.

001

188

d-is

omer

[B]/

[F]

�C

AA

Gd:

r�

0.70

,p

�0.

001

188

l-is

omer

[B]/

[F]

�C

AA

Gd:

r�

0.66

,p

�0.

001

188

Met

hoxy

prom

azin

e(P

TZ

/Psy

)K

A�

2.0

�10

624

78-

Met

hoxy

psor

alen

(A-P

sr)

16%

[114

]K

A�

2.1

�10

433

2

(con

tinu

ed)

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

Met

hotr

exat

e(A

-Cn)

1%[2

00]

295

N-M

ethy

limip

ram

ine

(Q)

42–6

1%[1

00]

426

N-M

ethy

ldep

trop

ine

(Q)

51%

[100

]K

A�

5.9

�10

542

6M

etoc

lopr

amid

e(A

-Em

)[B

]/[F

]�

CA

AG

485

Met

ocur

ine

(M-R

lx)

[B]/

[F]

�C

AA

G:

r�

0.94

,p

�0.

001

165

Met

opro

lol

(BB

,A

-HT

)6%

[66]

396

Mia

nser

in(A

-Dp)

%B

�C

AA

G:

r2�

0.56

,p

�0.

0536

174

%[1

50]

KA

�1.

1�

105

254

Mib

efra

dil

(CC

B,

A-H

T)

99%

486

Mif

epri

ston

e(A

-Pg,

AF)

93–9

8%48

7(R

U48

6)%

B�

CA

AG

KA

�8.

0�

106

488

Mito

xant

rone

(A-C

n)51

%[2

25]

nKA

�2.

0�

104

259

Mor

iciz

ine

(A-A

r)70

%48

9M

orph

ine

(Ag)

�20

%[5

0]31

14%

–5%

KA

�3.

7�

103

298

Mox

apri

ndin

e(A

R)

77%

[67]

;F

F�

iCA

AG

395

Nad

olol

(BB

,A

-HT

)10

%;

%B

�C

AA

Gd

490

Nal

idix

icac

id(A

B)

%B

�lo

w45

0N

alox

one

(A-N

r)�

20%

[50]

311

[B]/

[F]

�C

AA

G:

r�

0.76

,p

�0.

0149

1N

apro

xen

(NSA

ID)

2%[6

7]6

Nic

ardi

pine

(CC

B,

A-H

T)

91%

KA

�3.

4�

105

316

Nic

ergo

line

(V-D

,a 1

B)

KA

�1.

8�

104

492

Nif

edip

ine

(CC

B,

A-H

T)

51–7

6%[5

0–1

50];

%B

�C

AA

G49

3N

imet

azep

am(B

DZ

,A

-Cv,

M-R

lx)

KA

�0.

2�

105

246

Niz

atid

ine

(A-H

2)

36%

494

Nor

epin

ephr

ine

(Adr

)K

D�

1.4

�10

�4

75K

D�

5.4

�10

�5

76N

orge

stre

l(O

C)

64%

KA

�1.

4�

106

495

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Nor

trip

tylin

e(T

C,

A-D

p,Ps

y)[B

]/[F

]�

CA

AG

d:

r�

0.49

nKA

�6.

7�

105

149

KA

�1.

2�

105

253

KA

�1.

0�

105

350

Nor

zim

elid

ine

(see

Zim

elid

ine)

Nos

capi

ne(A

-Ts)

KA

�3.

2�

104

496

NQ

12(P

DE

I)�

20%

497

Ola

nzap

ine

(Psy

)77

%49

8O

prom

azin

e(P

TZ

,A

-Psy

)K

A�

0.7

�10

624

7�

62%

447

Oxa

zepa

m(B

DZ

,A

-Ax)

KA

�0.

3�

105

246

Oxp

reno

lol

(BB

,A

-HT

)%

B�

CA

AG

146

72%

;F

F�

iCA

AG:

r�

�0.

90,

p�

0.00

139

675

%[7

0]K

A�

1.9

�10

632

3O

xyco

done

(Ag)

5–10

%K

A�

4.1

�10

329

8Pa

clita

xel

(A-C

n)62

%[1

00]

468

Panc

uron

ium

(Q,

M-R

lx)

10%

[100

]42

6PC

R23

62(A

-Cg,

A-P

t)K

A�

3.3

�10

449

9Pe

nbut

olol

(BB

,A

-HT

)[B

]/[F

]�

CA

AG

341

93%

[75]

;[B

]/[F

]�

CA

AG

d:

r�

0.79

,p

�0.

01K

A�

1.2

�10

634

7Pe

ntaz

ocin

e(A

g)�

20%

[50]

311

Pera

zine

(PT

Z,

A-P

sy)

[F]

�iC

AA

Gd

KA

�3.

8�

105

500

KA

�1.

3�

106

247

94–9

9%[7

0]K

A�

7.2

�10

525

3[B

]/[F

]�

CA

AG

d:

r�

0.79

nKA

�4.

9�

105

253

FF

�iC

AA

G24

4M

etab

olite

s:N

-dem

ethy

lper

azin

e(D

esm

ethy

lper

azin

e)(P

TZ

,A

-Psy

)K

A�

1.5

�10

550

0Pe

razi

ne-s

ulfo

xide

KA

�1.

2�

104

500

Peri

ndop

ril

(AC

EI,

A-H

T)

41%

501

Met

abol

ite:

Peri

ndop

rila

t(A

CE

I,A

-HT

)�

20%

501

(con

tinu

ed)

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

Perp

hena

zine

(PT

Z,

A-P

sy)

FF

�iC

AA

Gd

185

85%

[80]

KA

�3.

4�

105

244

FF

�iC

AA

G:

r�

�0.

50,

p�

0.00

624

4K

A�

1.7

�10

624

7�

85%

447

Peth

idin

e(s

eeM

eper

idin

e)Ph

ency

clid

ine

(An)

10%

[50]

,17

%[1

00],

40%

[150

]11

2F

F�

iCA

AG;

%B

�C

AA

GK

A�

1.7

�10

411

264

%[7

5];

FF

�iC

AA

Gd:

r�

�.5

5,p

�0.

0135

5Ph

enob

arbi

tal

(A-C

v,Se

d)K

D�

8�

10�

214

Phen

othi

azin

e(P

TZ

)K

A�

1.2

�10

450

0Ph

enyl

buta

zone

(A-I

nf,

Ag)

KA

�5.

3�

103

1616

%[8

0]K

D�

1.9

�10

�4

161

27%

[200

]16

126

%[9

0]K

A�

3.5

�10

424

9K

D�

3.5

�10

�2

249

27%

[200

]29

5Ph

enyt

oin

(A-C

v)33

%[2

00]

187

FF

�no

iCA

AG

d41

5Ph

ysos

tigm

ine

�15

%[5

0]50

2(A

ChE

,A

IzD

)Pi

ndol

ol(B

B,

A-H

T)

65%

[90]

KA

�7.

1�

104

258

KD

�0.

7�

10�

525

831

%[6

6];

FF

�iC

AA

G:

r�

�0.

92,

p�

0.00

139

6Pi

pequ

alin

e(A

-Ax)

88%

[45]

KA

�4.

5�

105

503

Pira

rubi

cin

(A-C

n)46

%[2

25]

nKA

�1.

7�

104

259

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Prim

enol

(A-A

r)[B

]/[F

]�

CA

AG

d:

r�

0.96

,p

�0.

001

504

Pras

tero

nesu

lfat

e(A

ndrg

)13

%50

5Pr

azos

in(a

1B

,V

-D,

A-H

T)

[B]/

[F]

�C

AA

Gd:

r�

0.58

,p

�0.

005

419

83%

[62]

255

87%

[50]

,93

%[1

00]

KD

�0.

7�

10�

628

5%

B�

CA

AG:

r2�

0.95

,p

�0.

01K

D�

2.0

�10

�6

292

[B]/

[F]

�C

AA

Gd:

r�

0.97

KA

�5.

7�

105

292

Pred

niso

lone

(GC

)2–

44%

[25–

500]

;[B

]/[F

]�

CA

AG:

r�

0.91

nKA

�4.

0�

103

506

Prim

aqui

ne(A

-MI)

�70

%[1

50];

FF

�iC

AA

Gd

287

Prob

enec

id(U

rSc)

1%[2

00]

295

Proc

hlor

pera

zine

(PT

Z,

A-P

sy,

A-E

m)

KA

�1.

1�

106

247

Prog

abid

e(A

-Cv)

32%

[80]

KA

�3.

1�

104

333

Met

abol

ite:

SL75

102

12%

[80]

KA

�1.

6�

104

333

Prog

este

rone

(SX

H)

KA

�1.

1�

106

873

–85%

[90]

KA

�3.

2�

105

507

96%

487

Prom

azin

e(P

TZ

,A

-Psy

)K

A�

3.8

�10

450

0K

A�

1.9

�10

624

7Pr

omet

hazi

ne(A

-Hs,

A-E

m)

KA

�1.

2�

106

247

Prop

afen

one

(A-A

r)[B

]/[F

]�

CA

AG

d:

r�

0.83

KA

�6.

5�

105

404

92%

[88]

KA

�2.

9�

106

331

Ena

ntio

mer

s:R

-iso

mer

KA

�6.

2�

105

312

S-is

omer

KA

�8.

9�

105

312

Met

abol

ite5-

Hyd

roxy

prop

afen

one

46%

[88]

KA

�3.

1�

105

331

Prop

eric

iazi

ne(P

sy)

KA

�1.

3�

106

248

Prop

isom

ide

(A-A

r)85

%50

8Pr

opof

ol(A

n)54

%50

9

(con

tinu

ed)

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

Prop

rano

lol

(BB

,A

-HT

)F

F�

iCA

AG:

r�

�0.

79,

p�

0.01

72[B

]/[F

]�

CA

AG

d:

r�

0.88

nKA

�5.

4�

105

113

50–9

3%[2

0–4

00];

[B]/

[F]

�C

AA

G:

r�

0.97

nKA

�1.

1�

105

113

[B]/

[F]

�C

AA

G:

r�

0.98

,p

�0.

001

nKA

�2.

8�

105

162

FF

�iC

AA

Gd :

r�

�0.

5218

5[B

]/[F

]�

CA

AG

d:

r�

0.53

,p

�0.

01nK

A�

1.2

�10

520

2[B

]/[F

]�

CA

AG:

r�

0.86

,p

�0.

001

nKA

�4.

6�

105

189

82%

[50]

;92

%[1

50]

360

[B]/

[F]

�C

AA

Gd

360

FF

�iC

AA

Gd :

r�

�0.

77,

p�

0.00

132

7[B

]/[F

]�

CA

AG

d:

r�

0.77

,p

�0.

001

nKA

�2.

9�

105

327

FF

�iC

AA

Gd

397

[B]/

[F]

�C

AA

Gd:

r�

0.73

,p

�0.

01nK

A�

3.3

�10

541

5[B

]/[F

]�

CA

AG

d:

r�

0.66

,p

�0.

001

419

69%

[66]

;F

F�

iCA

AG:

r�

�0.

90,

p�

0.00

139

670

%[7

0]K

A�

2.4

�10

532

3F

F�

iCA

AG:

r�

�0.

35,

p�

0.05

184

83–9

5%[9

0]K

A�

8.4

�10

550

774

%[1

10]

314

83%

[80]

;F

F�

iCA

AG:

r�

�0.

78,

p�

0.00

151

0K

D�

1.3

�10

�4

465

KA

�1.

0�

105

446

KD

�9.

8�

10�

644

657

%K

A�

1.2

�10

531

6E

nant

iom

ers:

R(�

)d-

isom

er[B

]/[F

]�

CA

AG;

r2�

0.85

186

84%

[66]

313

70%

[110

]31

4[B

]/[F

]�

CA

AG:

r�

0.75

,p

�0.

001

315

78%

315

FF

�iC

AA

Gd

KA

�2.

73�

105

511

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS

HUMAN ALPHA-1-GLYCOPROTEIN 191S(

�)

l-is

omer

[B]/

[F]

�C

AA

Gr:

r2�

0.78

186

87%

[66]

313

77%

[110

]31

4[B

]/[F

]�

CA

AG:

r�

0.75

,p

�0.

001

315

79%

315

FF

�iC

AA

Gd

KA

�3.

4�

106

511

Prot

ript

ylin

e(T

C,

A-D

p)[B

]/[F

]�

CA

AG

243

Pyra

zina

mid

e(A

-TB

)12

%47

7Py

rim

etha

min

e(A

-MI)

�5

299

Qua

tern

ary

amm

oniu

m10

–70%

426

com

poun

ds(Q

)Q

uini

dine

(A-A

r)[B

]/[F

]�

CA

AG:

r�

0.88

KA

�2.

0�

105

349

53%

[50]

283

76%

[50]

,90

%[1

00],

95%

[200

]29

3Q

uini

ne(A

-MI)

FF

�iC

AA

Gd :

r�

�0.

53,

p�

0.00

0138

8%

B�

CA

AG:

r�

0.71

,p

�0.

001

210

39%

[70]

;[B

]/[F

]�

CA

AG:

r�

0.85

,p

�0.

005

389

87%

[50]

,95

%[1

00],

98%

[200

]29

3R

ebox

etin

e(A

D)

�98

%[2

00]

512

Rem

oxip

ride

(A-P

sy,

Toc

)F

F�

iCA

AG

d ;[B

]�

CA

AG

d40

6R

esin

ifer

atox

in(N

CA

)K

A�

0.3

�10

644

1R

etin

oic

acid

(Vit)

33%

[200

]29

5R

ifam

pici

n(A

-TB

/AB

)77

%[2

00]

187

70%

[100

]47

7R

ispe

rido

ne(A

-Psy

)85

[70]

;%

B�

CA

AG

190

Rito

drin

e(M

-Rix

)[B

]/[F

]�

CA

AG

513

RU

486

(see

Mif

epri

ston

e)S1

2363

(see

Vin

caal

kalo

ids)

S978

8(M

DR

M)

KA

�2.

5�

105

514

Salic

ylic

acid

(Ker

)�

2%[9

0]24

9�

1%[2

00]

295

SC52

151

(P-I

)75

%[2

00];

%B

�C

AA

G21

Sem

otia

dil

(CC

B)

�99

%27

1E

nant

iom

ers:

%B

:R

�S

271

Lev

osem

otia

dil

(S�

)K

A�

2.6

�10

727

2R

-sem

otia

dil

KA

�3.

2�

107

272

(con

tinu

ed)

Dru

g M

etab

olis

m R

evie

ws

Dow

nloa

ded

from

info

rmah

ealth

care

.com

by

Uni

vers

ity L

ibra

ry U

trec

ht o

n 02

/21/

13Fo

r pe

rson

al u

se o

nly.

ORDER REPRINTS


Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

SL75

102

(A-C

v)(s

eePr

ogab

ide)

Sota

lol

(BB

,A

-Ar)

�1%

396

Spir

onol

acto

ne(D

iur)

82%

[180

]K

A�

1.1

�10

544

0M

etab

olite

:se

eC

anre

none

Sufe

ntan

il(A

g)F

F�

iCA

AG:

r�

�0.

73,

p�

0.00

118

283

%[6

3]72

–93%

[50

–20

0];

%B

�C

AA

G26

1Su

lfinp

yraz

one

(UrS

c)K

A�

2.4

�10

316

30%

[200

];lo

gK

A�

�4.

38K

D�

4.2

�10

�5

295

Sulin

dac

(NSA

ID)

8%[8

0];

15%

[200

]16

1T

acri

ne(A

lzD

)23

%51

5T

acro

limus

(Im

m-S

upp)

39%

[100

]51

6(F

K50

6)97

%[1

00]

517

Tam

sulo

sin

(a1B

)C

T�

CA

AG

518

Tax

ol(A

-Cn)

FF

�iC

AA

G;

AU

CT

�C

AA

G;

%B

AA

G�

%B

HSA

519

Ter

tato

lol

(BB

,A

-HT

)[B

]/[F

]�

CA

AGr:

r�

0.75

nKA

�2.

4�

105

437

Ster

eois

omer

s%

B:

S(�

)�

R(�

)31

7T

esta

ster

one

(SX

H)

KA

�4.

5�

105

9K

A�

3.0

�10

525

2T

heop

hylli

ne(B

D)

12%

270

Thi

azin

amiu

m(Q

)45

–71%

[100

]42

6T

hior

idaz

ine

(PT

Z,

A-P

sy)

%B

�C

AA

GK

A�

5.5

�10

728

9K

A�

8.0

�10

544

6K

D�

1.2

�10

�6

446

Met

abol

ites

(A-P

sy):

Side

-cha

insu

lfox

ide

FF

�iC

AA

G:

r�

�0.

54,

p�

0.03

416

KA

�4.

9�

106

289

Rin

gsu

lfox

ide

FF

�iC

AA

G:

r�

�0.

62,

p�

0.02

416

KA

�2.

9�

106

289

Side

-cha

insu

lfon

eK

A�

1.4

�10

728

9

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Thi

othi

xene

(PT

Z,

A-P

sy)

KA

�2.

4�

105

446

KD

�4.

2�

10�

644

6T

iane

ptin

e(A

-Dp)

KA

�3.

7�

104

405

Tic

lopi

dine

(A-C

g,A

-PI)

KA

�8.

9�

104

499

Tim

egad

ine

(NSA

ID)

%B

�hi

gh;

FF

�iC

AA

Gd;

[B]

�C

AA

Gd:

r�

0.88

520

Tim

olol

(BB

,A

-HT

)27

%[6

6];

FF

�iC

AA

G:

r�

�0.

88,

p�

0.00

139

6T

olm

etin

(NSA

ID)

1%[2

00]

161

Tor

emif

ene

(A-C

n)�

20%

521

Tri

amte

rene

,p-

hydr

oxy-

sulf

ate

(Diu

r)[B

]/[F

]�

CA

AG:

r�

0.72

,p

�0.

0516

Tri

azol

am(B

DZ

,Se

d)89

%[1

00];

94%

[230

];%

B�

CA

AG

403

[B]/

[F]

�C

AA

Gd:

r�

0.82

,p

�0.

001

KA

�2.

1�

105

403

Tri

flupe

razi

ne(P

TZ

,A

-Psy

)92

%[8

0]K

A�

6.0

�10

524

4K

A�

1.8

�10

624

7T

riflu

prom

azin

e(P

TZ

/A-P

sy)

KA

�2.

5�

106

247

d-T

uboc

urar

ine

(Q,

M-R

lx)

[B]/

[F]

�C

AA

G:

r�

0.98

,p

�0.

001

165

54%

187

12–1

8%42

6V

alpr

oic

acid

(A-C

v)�

2%[9

0]24

9V

alsa

rtan

(AR

B/A

-HT

)22

%52

2V

anco

myc

in(A

B)

21%

[80]

114

[B]/

[F]

�C

AA

G:

r�

0.63

,p

�0.

001

386

Vel

nacr

ine

(Alz

D)

%B

�C

AA

G35

8V

erap

amil

(CC

B/A

-HT

/A-A

r)90

%[5

0];

94%

[150

]52

3[B

]/[F

]�

CA

AG

d:

r�

0.83

nKA

�1.

2�

105

523

Ena

ntio

mer

s:R

(�)

isom

er83

%31

5%

B�

CA

AG:

r�

0.75

,p

�0.

001

315

KA

�2.

5�

10�

626

699

.92%

318

(con

tinu

ed)

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Tab

le3.

Con

tinue

d

Dru

g/L

igan

da

Bin

ding

Dat

abB

indi

ngC

onst

antc

Ref

.

S(�

)is

omer

99.8

6%31

5%

B�

CA

AG:

r�

0.78

,p

�0.

001

315

nKA

�5.

0�

10�

626

677

%31

8V

inbl

astin

e(A

-Cn)

�99

%[7

2]K

A�

9.4

�10

652

445

%[1

00]

468

Vin

caal

kalo

ids:

(A-C

n)K

A�

1.5

�10

4–

7.8

�10

631

9S1

2363

KA

�6.

0�

105

525

Vin

olre

lbin

e(A

-Cn)

�20

%52

5V

X-4

78[1

41W

94](

P-I)

89%

[72]

KD

�4

�10

�6

22W

arfa

rin

(A-C

g)40

%[9

0];

249

[B]/

[F]

�no

CA

AG:

r�

0.31

,p

�0.

1K

A�

2.3

�10

524

988

%[9

0]K

A�

1.2

�10

528

4Z

idov

udin

e(A

-Vr,

AID

S)0%

526

Zile

uton

Bca

p AA

G�

3�

Bca

pH

SA52

7Z

imel

idin

e(A

-Dp)

FF

�iC

AA

Gd :

r�

�0.

69nK

A�

4.5

�10

538

2M

etab

olite

(N-d

ealk

ylat

ed):

Nor

zim

elid

ine

(A-D

p)F

F�

iCA

AG

d :r

��

0.71

nKA

�0.

5�

105

382

Zol

pide

m(S

ed)

66%

410

Zop

iclo

ne(�

)(H

yp,

Sed)

�50

%32

0Z

orub

icin

(A-C

n)64

%[2

25]

259

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aD

rug

clas

sific

atio

n:A

-Ar

�an

tiarr

hyth

mic

drug

;A-A

st�

antia

sthm

adr

ug;A

-Ax

�an

tianx

iety

agen

t;A

B�

antib

iotic

;a 1

BI

�al

pha 1

adre

nerg

icre

cept

orbl

ocke

r;A

CE

I�an

giot

ensi

n-co

nver

ting

enzy

me

inhi

bito

r;A

-Cg

�an

ticoa

gula

nt;A

-Cn

�an

tican

cerd

rug;

A-C

v�

antic

onvu

lsiv

eag

ent;

A-D

p�

antid

epre

s-sa

nt;

A-E

m�

antie

met

ic;

AF

�ab

ortif

acie

nt;

A-F

n�

antif

unga

lag

ent;

A-I

nf�

anti-

infla

mm

ator

yag

ent;

Adr

�ad

rene

rgic

agen

t;A

g�

anal

gesi

c;A

-Hs

�an

tihis

tam

ine;

A-H

1�

antih

ista

min

eH

1-bl

ocke

r;A

-H2

�an

tihis

tam

ine

H2-

bloc

ker;

A-H

T�

antih

yper

tens

ive

agen

t;A

lzD

�D

rug

used

inpa

tient

sw

ithA

lzhe

imer

’sdi

seas

e;A

-MI

�an

timal

aria

lag

ent;

An

�an

esth

etic

;A

ndrg

�an

drog

en;

A-N

r�

antin

arco

ticdr

ug;

A-P

r�

antip

yret

ic;

A-P

g�

antip

roge

stin

agen

t;A

-Psr

�an

tipso

rias

isdr

ug;A

-Psy

�an

tipsy

chot

icdr

ug;A

-Pt�

antip

late

letd

rug;

AR

B�

angi

oten

sin

IIre

cept

orty

peA

1bl

ocke

r;A

-Sr

�an

tiser

oton

indr

ug;

A-T

B�

antit

uber

culo

sis

drug

;A

-Ts

�an

titus

sive

;A

-Vr

�an

tivir

alag

ent;

BB

�be

ta-a

dren

ergi

cre

cept

orbl

ocke

r;B

D�

bron

chod

ilato

r;B

DZ

�be

nzod

iaze

pine

;C

CB

�ca

lciu

mch

anne

lbl

ocke

r;C

hl�

chol

iner

gic

agen

t;C

St�

cort

icos

tero

id;

CT

�ca

rdio

toni

c;cV

-D�

coro

nary

vaso

dila

tor;

Diu

r�

diur

etic

;G

C�

gluc

ocor

ticoi

d;K

er�

kera

toly

ticag

ent;

LA

n�

loca

lan

esth

etic

;L

LD

�lip

id-l

ower

ing

drug

;M

DR

M�

mul

tiple

-dru

gre

sist

ance

mod

ifier

;M

-I�

mon

oam

ine

oxid

ase

inhi

bito

r;M

R�

mus

cle

rela

xant

;M

sc�

mic

ella

neou

s;m

Tr

�m

inor

tran

quliz

er;

NC

A�

noci

cept

ive

agen

t;M

-Rlx

�m

uscl

ere

laxa

nt(n

euro

mus

cula

rbl

ocke

r);

NSA

ID�

nons

tero

idal

antii

nflam

mat

ory

drug

;O

C�

oral

cont

race

ptiv

e;pA

-Cv

�an

ticon

vuls

ive

agen

t(p

rodr

ug);

PDE

I�

phos

podi

este

rase

A2in

hibi

tor;

P-I�

prot

ease

inhi

bito

r(dr

ugs

used

inA

IDS

patie

nts)

;Psy

�dr

ugus

edin

psyc

hiat

ry;P

TZ

�ph

enot

hiaz

ine;

Q�

quar

tern

ary

amm

oniu

mco

mpo

und;

seda

tive;

SXH

�se

xho

rmon

e;

TC

�tr

icyc

lic;

Toc

�to

coly

ticag

ent;

UrS

c�

uric

osur

icag

ent;

Vit

�vi

tam

in;V

-D�

vaso

dila

tor.

bT

hebi

ndin

gva

lues

repo

rted

are

atph

ysio

logi

cal

conc

entr

atio

nsof

the

drug

san

dA

AG

conc

entr

atio

nfo

und

inno

rmal

volu

ntee

rs,e

xcep

tas

othe

rwis

eno

ted

inbr

acke

ts:

�co

ncen

trat

ion

ofA

AG

inm

g/d

L(1

µM�

4.5

mg

/dL

).T

hedi

ffer

ence

sin

bind

ing

para

met

ers

may

bedu

eto

the

tech

niqu

eem

ploy

edfo

rm

easu

ring

bind

ing,

the

tem

pera

ture

,and

time

for

equi

libra

tion,

the

met

hod

used

for

calc

ulat

ing

the

para

met

ers,

and

the

orig

inof

AA

Gor

plas

ma

cont

aini

ngth

egl

ycop

rote

in.

Abb

revi

atio

ns:

[B]

�co

ncen

trat

ion

ofth

ebo

und

drug

;[F

]�

conc

entr

atio

nof

the

free

drug

;B

�bo

und

drug

;C

AA

G�

conc

entr

atio

nof

AA

G;

FF

�fr

eedr

ug;[

B]/

[F]

�C

AA

G�

conc

entr

atio

nra

tioof

boun

d/fr

eedr

ugis

prop

ortio

nalt

oth

eco

ncen

trat

ion

ofA

AG

;FF

�iC

AA

G�

free

drug

isin

vers

ely

prop

ortio

nal

toth

eco

ncen

trat

ion

ofA

AG

;[B

]/[F

]�

noC

AA

G�

conc

entr

atio

nra

tioof

boun

d/fr

eedr

ugis

not

prop

ortio

nal

toth

eco

ncen

trat

ion

ofA

AG

;K

A�

bind

ing

(ass

ocia

tion)

cons

tant

;K

D�

diss

ocia

tion

cons

tant

;n

KA

�pr

oduc

tof

num

ber

ofbi

ndin

gsi

tes

and

KA;

nK

p�

affin

ityco

nstr

aint

.cK

Ade

term

ined

byth

eSc

atch

ard

plot

.d

Bin

ding

data

obta

ined

with

plas

ma/

seru

msa

mpl

es(f

rom

patie

nts

orhe

alth

ysu

bjec

ts)

cont

aini

ngva

ryin

gam

ount

sof

AA

G;

inso

me

case

sva

ryin

gam

ount

sof

AA

Gw

ere

adde

dto

the

sam

ples

prio

rto

bind

ing

stud

ies.

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results of the studies which show inverse correlation between FF (or direct correla-tion between FB) and AAG concentration for a number of drugs: acridine-4-car-boxamide, alfentanil, alprenolol, amitriptyline, apazone, aprindine, bupivacaine,carbamazepine, chlorpromazine, clindamycin, cloxacillin, cocaine, diazepam, di-phenhydramine, disopyramide, docetaxel, doxepin, erythromycin, etidocaine, fen-tanil, fluconazole, gallopamil, hydroxychloroquine, imipramine, indapamide, leri-setron, lidocaine, lofentanil, meperidine, methadone, metoclopramide, mianserin,mifepristone, moxaprindine, nadolol, naloxone, nifedipine, nortriptyline, oxpranol-ol, penbutolol, perazine, perphenazine, phencyclidine, pindolol, prazosin, prednis-olone, primaquine, propafenone, propranolol, quinidine, quinine, remoxipride, ri-todrine, tamsulosin, timegadine, timolol, triazolam, vancomycin, velnacrine, andzimelidine (Table 3).

For some drugs, both albumin and AAG contribute about equally towardbinding (e.g., amitriptyline, chloroquine, dipyridamole, taxol, and paclitaxel). Onthe other hand, for some drugs (Table 3), especially the acidic drugs, binding toAAG is low or inconsequential (161,185,249,295). These drugs include some, butnot all, nonsteroidal anti-inflammatory drugs, antibiotics, beta-blockers, benzodi-azepines, diuretics, steroids, narcotic analgesics, and antifungal agents (Table 3).

A number of drugs with a quaternary ammonium group, such as alcuronium,atracurium, hexafluorenium, thiazinamium, pancuronium, and d-tubocurarine,also bind to AAG (Table 3), often with an affinity higher than for albumin. Thecontribution of AAG to the overall plasma binding of drugs with moderate affinityfor AAG (Table 3) is dependent on the relative binding to albumin and the concen-tration of AAG.

Not all weakly basic drugs have high binding affinity to AAG. For example,the binding affinity of cicletanine is higher for albumin than for AAG (296), andthe binding of almitrine (297), morphine (298), oxycodone (298), and pyrimeth-amine (299) to AAG is low and inconsequential with regard to total drug bindingin plasma. Although the acidic drugs do not generally bind significantly to AAG,there are some exceptions, such as apazone (284), indapamide (300,301), andwarfarin (283,284). For some acidic drugs, despite low binding to AAG, the KA

may be high enough to suggest that binding to AAG will contribute significantlyto the overall plasma protein binding of the drug (283).

2. Enantioselective Binding of Optical Isomers of Drugs to AAG

Stereoselective binding of the optical isomers of several drugs to AAG hasbeen demonstrated for acenocoumarol (S � R) (302), bupivacaine [R(�) � S(�)](303); carvedilol (R � S) (273), chloroquine [(�) � (�)] (304), chlorpheniramine[S(�) � R(�)] (305), disopyramide [S(�) � R(�)] (266,306), gallopamil (307),hydroxychloroquine (308,309), isradipine [S(�) � R(�)] (310), methadone(d � l) (188,311), propafenone (S � R) (312), propranolol [S(�) � R(�)](186,191,266,313–316), semotiadil (R � S) (271,272), tertatolol [S(�) � R(�)](317), verapamil [R(�) � S(�)] (266,315,318), vinca alkaloids (319), and zopi-

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clone (320). However, in most cases, stereoselective binding (of the enantiomers)of drugs to AAG has no clinical significance (316).

D. Displacement of Drugs from Binding Site(s) on AAG by OtherSubstances: Other Drug–Drug Interactions

A ligand with higher affinity (at a certain concentration) can displace anotherone with lower affinity from the high affinity–low capacity binding site on AAG.Westphal and associates (9,252) carried out the first study of the competition forbinding to AAG with steroids. Later, comprehensive studies of drug-binding inter-actions were carried out by a number of investigators. Of the many drugs studied,disopyramide is the most potent in displacing imipramine (241), chlorpromazine(243), and some analgesics and anesthetics (5,321) from AAG binding sites, sug-gesting its high binding affinity for AAG. Studies of displacement with local anes-thetics (bupivacaine, lidocaine, and mepivacaine) show that bupivacaine has thehighest affinity for AAG (245,322).

In a study of the displacement of antidepressants and alpha-1-adrenergicreceptor antagonists from AAG binding sites, the following potency order wereobserved for displacing prazosin (255): trazodone � prazosin � doxazosin �propranolol � doxepin � amoxapin � trimazosin � amitriptyline � imipra-mine � nortriptyline � desipramine � nomifensine � bupropion � maprotiline.For displacing imipramine (255), the order was prazosin � amitriptyline � pro-pranolol � doxazosin � nortriptyline � desipramine � trimazosin. Methadonewas displaced from AAG binding site by most lipophilic basic drugs, especiallythioridazine (489). These studies can give an estimate of binding affinity for anumber of drugs for which binding data are not available. The data from suchstudies are important in determining the pharmacokinetic and pharmacodynamicconsequences of multiple-drug therapy. Drug displacement studies have also beenused to characterize the binding sites on AAG (241,243,245,251).

As mentioned earlier (Sec. IV.B.2), the plasticizers di-(2-ethylhexyl)-phthal-ate and tris-(2-butoxyethyl)-phosphate (TBEP), present in rubber stoppers of cer-tain blood collection tubes, can leach out into the blood and cause displacementof many drugs (e.g., amitriptyline, beta-blockers, ketamine, primaquine, quinidine,etc.) from AAG binding sites (16,31,283,286–288,323).

V. PHARMACOKINETIC AND CLINICAL ASPECTS OF DRUGBINDING TO AAG

A. Pharmacokinetic Considerations

In general, the binding of a drug to AAG can have important pharmacoki-netic implications, especially for a drug which is (1) highly bound to AAG (bind-ing � 80% and/or KA � 105 M�1), (2) its apparent volume of distribution (VD)is small, and (3) AAG is the main binding protein in plasma (1–4,10–12,324,325).

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For a drug with binding affinity for AAG higher or equal to that to albumin, FF

is influenced significantly if there is a rise in AAG levels (such as in inflammation)and/or a decrease in albumin concentration (as in hypoalbuminemia) in vivo (284).

The binding (or CF/CT ratio) of drugs to AAG is dependent on a number offactors, including plasma AAG concentration. Because plasma AAG levels showlarge fluctuations (both decreases and increases) under various physiological andpathological conditions, binding of drugs, mainly basic and neutral, will also bealtered, resulting in a change in CF. For example, in inflammatory diseases, such asCrohn’s disease and rheumatoid arthritis, in which plasma AAG are dramaticallyincreased, a significant decrease is observed in the CF of alfentanil (326), chlor-promazine (327), disopyramide (328), lidocaine (329), propranolol (327), and soforth. In situations where albumin concentration decreases, the CF of a drug whichbinds to both AAG and albumin will depend on the concentration of AAG (284).Therefore, the overall changes in the pharmacokinetic parameters of a drug willdepend on the relative contribution of albumin and AAG to drug binding andtransport of the drug into red blood cells (330–333).

Increased (or decreased) binding to AAG may not necessarily alter CF ifbinding to albumin is simultaneously decreased (or increased). In addition, anincrease (or decrease) in CF would reduce (or increase) the erythrocyte/plasmadrug concentration ratio. Thus, total blood levels of drugs may not change muchwith changes in plasma AAG levels (334). In addition, an increase or decreasein FF does not automatically mean an increase or decrease in CF. For drugs almostexclusively bound to AAG, an increase (or decrease) in binding will tend to de-crease (or increase) the VD of the total drug (bound plus free drug); the variationin VD is expected to be more or less proportional to the changes in FF.

The total clearance of a drug (Cl) may or may not be altered by changes inthe binding to AAG, because it will depend on the initial clearance of the drug(first-pass effect) and the avidity of protein binding. Because the Cl of a drug isdependent on its hepatic extraction (13), and if the latter is, in turn, dependenton its FU, and variation in FF (e.g., by a change in AAG levels) will lead to analteration in CT, but without any effect on CF, and, thus, there should not be anychange in the pharmacological effect. However, if drug extraction is dependenton hepatic flow, a variation in FF will lead to a change in CF (but not in CT), andhence a change in pharmacological effect is expected. For example, an increasein plasma AAG level (postsurgery) resulted in a decrease of CF , VD, and Cl oflidocaine in vivo (206). The effect of an alteration in plasma AAG levels onplasma elimination half-life (T1/2) will depend on changes in Cl and VD.

An important pharmacokinetic consideration related to the binding affinityof AAG is for drugs whose metabolism is influenced by binding (3). For example,Schneider et al. (335) raised the question of whether increased binding of propran-olol in patients with elevated levels of AAG protected the drug from first-passeffect. The in vivo studies of Huang and Oie (336) showed that changes in proteinbinding of disopyridamole by infusion of increased amounts of human AAG in-fluenced the hepatic clearance of the drug (in rabbits), a situation likely to occurin humans with elevated plasma AAG.

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B. Clinical Implications

1. Influence of Changes in Plasma AAG Levels

Changes in plasma levels of AAG in many physiological or pathologicalconditions may significantly alter not only the pharmacokinetics but also the phar-macodynamics of drugs, especially for those for which AAG is the main bindingprotein in plasma. In many disease states in which plasma AAG levels rise, theCF of drugs highly bound to AAG is expected to decrease significantly (due toincreased binding), resulting in lower efficacy. Thus, therapeutic monitoring ofCT of drugs in patients with elevated AAG levels may not be sufficient to predictefficacy, especially for drugs that are highly bound to AAG. In such cases, drugCT may be in the therapeutic range or even elevated (due to increased bindingcapacity), but the CF of the drug will be lower than in patients with normal levelsof AAG. This situation may necessitate adjustment of dosages upward, based onthe CF, to obtain the desired therapeutic/pharmacological effect. For example,the mean dosage requirement of alfentanil for anesthesia in patients undergoingabdominal surgery was found to be almost two times higher in patients withCrohn’s disease than in patients without inflammatory disease (326). The reported‘‘resistance’’ to atracurium, a neuromuscular blocking drug, in a cancer patientundergoing gastric surgery was due to a decrease in the CF of the drug (337). Arise in plasma AAG levels (such as in infection) may decrease the CF of an antibi-otic (such as clindamycin) below the minimum inhibitory concentration for a num-ber of pathogens, rendering drug therapy ineffective (338) and necessitate com-pensatory increase in the dosage. Similarly, the antiplatelet effect of dipyridamolewould be attenuated by an increase in plasma AAG level (339).

Other examples in which drug dosages may have to be uptitrated includefluconazole (340), penbutolol (341), and propranolol (342) in cancer patients, al-fentanil (326) and propranolol (327) in patients with Crohn’s disease, quinidine(343) in patients with myocardial infarction, lidocaine (206) in patients undergoingsurgery, disopyramide in patients with arrhythmia (344), and fluconazole (345)in patients with chronic renal failure.

Some drugs may be become ineffective when given at normal therapeuticdoses because of elevated AAG levels in plasma. For example, an increase inplasma AAG level in HIV patients with an underlying infection could result inincreased binding and, thus, decreased efficacy of the protease inhibitors, the im-portant component of the life-prolonging drug cocktail used in the treatment ofAIDS. In vitro studies have shown that the inhibitory effect of protease inhibitorson the replication of both wild-type and mutant HIV-1 virus was abolished bythe addition of human AAG (18–20,24). Therefore, the doses of these drugs haveto be increased to prevent treatment failure in situations where plasma AAG levelsare high, such as due to concurrent bacterial infection, inflammation, and so forth.It may be noted that the in vivo efficacy of not all protease inhibitors is affectedby protein binding (22–24).

Therapeutic drug monitoring is generally recommended for drugs with anarrow therapeutic window. However, in patients with elevated AAG levels, the

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CT of a drug (mainly bound to AAG may actually be higher than that in patientswith normal levels of AAG, and, yet, patients may not exhibit toxic effects dueto the reduced CF of the drug (210,343). For example, in patients with high AAGlevels, the CT of lidocaine (free plus bound) were more than twofold higher thanin those with normal AAG levels, yet no clinical adverse effects were observedin such patients because the CF was about the same in the two groups (329,334).Plasma levels of propranolol (346) and alfentanil (326) were high in patients withCrohn’s disease, and plasma levels of quinine were high in patients with malaria(210), but the CF of the drugs was appropriate. Thus, it might be an error to lowerdosages of these drugs in such conditions, merely based on the measurement ofthe CT of the drug.

In some disease states, such as nephrotic syndrome (138) and hepatic cirrho-sis (347), plasma AAG levels may or may not rise, but the binding capacity ofthe glycoprotein is reduced. This may result in lower overall binding and higherCF of some drugs, such as disopyramide (138), and penbutolol (347), requiringdownward adjustment of dosages of these drugs. The reported higher incidenceof adverse effects of bupivacaine in obstetric patients was likely due to the higherCF of the drug as a result of decreased plasma AAG levels (199). In patients withhepatic disease, the dose of an analgesic (such as alfentanil) should be decreasedto compensate for the decreased binding of the drug (due to decreased plasmaAAG levels) (348). Therefore, in diseases in which plasma AAG levels are ex-pected to be lower than normal, therapeutic monitoring of CF is suggested fordrugs which are highly bound to AAG and have a narrow therapeutic window.

The binding of a drug is affected by the pH: The binding of basic drugs willincrease with increase in pH (112,115,291,349–351). Changes in binding of drugs,especially those with a narrow therapeutic window, may be clinically relevant inpathological conditions in which plasma (tissue) pH changes, such as in respira-tory and metabolic acidosis and alkalosis.

Because of the low levels of AAG in fetal and neonatal serum, the higherCF of basic drugs is expected in the fetus and in neonates than in the mother(170,178,180,352). Therefore, careful therapeutic monitoring of CF of the drugin plasma of mothers is recommended to avoid indirect drug toxicity to the fetusor the neonate. This is more important for drugs which are highly bound to AAGand which cross the placenta and/or are secreted into milk. In addition, drugs witha low therapeutic window (such as lidocaine) administered to the neonates shouldbe carefully monitored to avoid toxicity (170).

The extent of transport of a drug into brain (by passive diffusion) and itsequilibration and, thus, its pharmacologic and toxic effect in the central nervoussystem is, in general, dependent on the magnitude of plasma protein binding (353,354). For some drugs (e.g., phencyclidine), the fraction bound to AAG in plasmais not available for transport across the blood-brain barrier (355), whereas forothers (such as propranolol), the bound drug is available for transport into thebrain (356). Furthermore, for several drugs for which AAG is the main bindingprotein, the CF (the fraction available for transport into the brain) may not neces-sarily depend on the total binding to AAG, but on the fractional binding to AAG

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variants (129,133,263). For example, for drugs which bind exclusively to the vari-ant A of AAG (such as disopyramide, imipramine, and methadone), transport intothe brain is significantly lower than for those which bind to both the variant Aand the variant F*1/S (e.g., chlorpromazine and propranolol), or preferentiallyF*1/S (e.g., mifepristone) (265).

Interethnic differences in drug responsiveness can be accounted for, at leastin part, by differences in drug binding to AAG; the levels of the protein may bedifferent in different ethnic groups (72). Alteration in plasma AAG may also havesignificant effect on the CF of endogenous substances (such as catecholamines,corticosteroids, etc.) that bind to AAG, resulting in an abnormal physiologicalresponse.

2. Effect of Drug–Drug and Drug–Endogenous Substance Interactions

Drug–drug interactions at the binding site(s) have important clinical implica-tions, especially for drugs with a low therapeutic window. A drug with a higheraffinity for AAG may displace another drug with a lower affinity, thereby increas-ing the CF of the lower-affinity drug and thus resulting in increased pharmacologi-cal activity (therapeutic and toxic). For example, because bupivacaine displacesmepivacaine (322) and lidocaine (245) from AAG binding sites, simultaneousadministration of bupivacaine with the other two local anesthetics would result inhigher than expected CF of mepivacaine and lidocaine, respectively. This situationwould increase the risk of systemic toxicity. Similarly, displacement of lidocaineby disopyramide would result in higher than expected CF of lidocaine with a poten-tial for adverse effect (321).

On the other hand, drug displacement interaction may increase the efficacyof a drug; for example, the cytotoxicity of the antifolate CB3717 is potentiatedby the intentional coadministration of dipyridamole (357), as the latter displacesthe antifolate from AAG binding sites, thus increasing the CF of the drug. Anincrease in plasma AAG levels (such as in some cancers and other diseases) wouldattenuate the potentiating effect of dipyridamole (357). In in vitro binding studieswith AAG, disopyramide increased the FF of a protease inhibitor KNI-272 14-fold (23). Such drug interactions may potentially be used clinically to improvethe efficacy of selected drugs.

It is expected that displacement by drugs of endogenous substances withsignificant binding to AAG would increase plasma levels of the endogenous com-pounds and thus may lead to abnormal physiological effect. Also, the presenceof abnormal levels of endogenous substances in certain conditions may displacedrugs from AAG binding sites and increase plasma CF, which may result in en-hanced drug effect. For example, the levels of bilirubin increase in hyperbilirubi-nemia of hepatitis or cirrhosis, plasma levels of free fatty acids rise after a fattymeal or after heparin administration, and plasma levels of unknown substancesincrease in uremia and renal failure. These interactions may be clinically signifi-cant.

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VI. CONCLUSIONS

This review demonstrates that the glycoprotein AAG, present in almost allbody fluids, has significant affinity for many basic and neutral drugs. Althoughalbumin is the main plasma protein involved in the binding/transport of drugsand endogenous substances, the next most important protein is AAG. BecauseAAG is the predominant binding protein for many compounds, like albumin itmay also have a role in protecting cells and tissues and in the transport of noxioussubstances that have entered plasma. Measurement of drug binding to AAG isbecoming important as the number of drugs shown to bind significantly to AAGis growing. Binding to AAG may significantly influence drug pharmacokineticsand pharmacodynamics.

Because AAG is an acute-phase protein, its concentration increases in manydiseases, which, in turn, influences the binding of certain drugs and their kinetics.This may necessitate modification of dosages of drugs with narrow therapeuticwindow.

Years ago, we suggested (1) that before a new drug is tested in man, compre-hensive studies should include measurement of physicochemical properties, includ-ing its binding to human plasma (serum) and albumin. Now, we would like to extendthis suggestion to include determination of drug binding to either purified humanAAG or plasma containing various concentrations of AAG. The new automatedrapid method for drug binding (280) can facilitate such determinations. Further, ifbinding of a test drug to AAG is significant, then measurement of plasma levelsof AAG may be needed in human Phase II and III investigations. In addition, be-cause multiple pharmacy is commonly employed, we recommend that limited drug–drug interactions, based on competitive binding to AAG for a test drug, be investi-gated if the affinity of the test drug for AAG exceeds that for albumin. In ouropinion, all studies of binding should be carried out at 37°C, pH 7.4, with physiolog-ical concentrations of AAG and therapeutic concentrations of the drugs for the datato be clinically relevant. Finally, in limited cases, therapeutic drug monitoringshould include the measurement of the CF of the drug in plasma or serum.

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174. Alt, R.; Erny, P.; Messer, J.; Willard, D. Neonatal Bacterial Infections. KineticStudy of C-Reactive Protein and Orosomucoid. Presse Med. 1984, 13, 1373–1376(in French).

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224. Briggs, M.H.; Briggs, M. Effect of Oral Ethinylestradiol on Serum Proteins inNormal Women. Contraception 1971, 3, 381–387.

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242. Muller, W.E. Drug Binding Sites on Human Alpha 1-Acid Glycoprotein. Prog.Clin. Biol. Res. 1989, 300, 363–378.

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250. Essassi, D.; Zini, R.; Tillement, J.-P. Use of 1-Anilino-8-naphthalene Sulfonate asa Fluorescent Probe in the Investigation of Drug Interactions with Human Alpha-1-acid Glycoprotein and Serum Albumin. J. Pharm. Sci. 1990, 79, 9–13.

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372. Fiotti, N.; Giansante, C.; Ponte, E.; Delbello, C.; Calabrese, S.; Zacchi, T.; Dobrina,A.; Guarnieri, G. Atherosclerosis and Inflammation. Patterns of Cytokine Regula-tion in Patients with Peripheral Arterial Disease. Atherosclerosis 1999, 145, 51–60.

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HUMAN ALPHA-1-GLYCOPROTEIN AND ITS INTERACTIONS WITH DRUGS12 †,‡