MediChem 세미나 일정

2. Advanced of Good Drug-Like Proper-

ties

2013. 09. 06Lee,Sang-Hwi

Drug–like properties for Drug discovery projects

Stage of drug discovery, primary goals, and major activity

• SAR : structure–activity relationship ( 구조 - 활성관계 )• SPR : structure–property relationship ( 구조 - 물성 관계 )

3. Barriers to Drug Expo-sure

in Living Systems

2013. 09. 06Lee,Sang-Hwi

Introduction to Barriers

• Physiological barriers reduce the amount of dosed compound that reaches the target.

• Barriers include membranes, pH, metabolic enzymes, and transporters.

• Good properties enable good absorption, distribution, low metabolism, reason-able elimination, and low toxicity.

Drug dosing routes

① More frequent dosing (if the half-life is short)② Higher doses (if the bioavailability is low)③ Administration by a different route (if absorption is low)④ A different vehicle or formulation (if solubility is low)

per os

3.3 Barriers in the Mouth and Stomach

stomach duodenum jejunum ileum

3.4 Gastrointestinal Tract Barriers

화합물의 용해도는 pH 와 분자의 pKa 의 함수이다 . 염기성 화합물은 pH 가 산성인 위와 장상부를 거쳐 주로 전하를 가진 양이온 상태를 가진다 . 전하를 가진 형태가 되면 전하를 가지지 않는 형태보다 좀더 수용성이므로 좋은 용해도를 나타낸다 . 산성약물은 위와 장 상부에서는 전하를 가지지 않으므로 용해도는 산 영역에서는 제한적이다 . ( 위장과 상부장에서 중립이다 .) pH 가 소장을 통하여 증가하면서 산성약물의 음이온 형태의 상대적인 양 증가로 높은 용해도를 가진다 .

•막 투과성은 소장의 주요 흡수 장벽이다 . • 투과성은 소장 지역의 pH 와 화합물의 pKa 에 따라 달라진다 . • 중성 분자는 전하를 가진 이온형태보다 훨씬 더 투과성이 있으나 용해도가 떨어진다 . • 따라서 투과성과 용해도는 pH 에 반비례한다 . • 소장에서 , 약물 분자는 크게 양분의 흡수를 향상 해부학을 발생한다 . • 소장 루멘의 내부 표면적은 세 가지 형태 기능에 의해 약 400 배 향상된다 . • 소장 루멘의 길이를 따라 안쪽 표면을 따라 기복이 시작되어 아래로 주름이 있다 . • 융모는 소장 루멘에 1mm 를 투영하여 표면 영역에 추가 할 수 있다 .

3.4.1 Permeation of the Gastrointestinal Cellular Membrane

(A) 수동 확산 (passive diffusion) : 분자는 지질 이중층의 세포막과 세포질을 통해 확산된다 . (B) endocytosis:(C) uptake transport (D) paracelluar transport: 분자량 (180Da) 이 적거나 polar 물질이 pore 또는 channel 을 통하여 투과(E) efflux transporter

3.4.2 Passive Diffusion at the Molecular Level

• Molecules with a larger molecular size do not pass through the tightly packed region as readily as smaller molecules.

• Molecules with higher lipophilicity typically are more permeable than less lipophilic molecules through the highly nonpolar central core of the lipid bilayer membrane.

3.4.3 Metabolism in the Intestine

• Drug molecules can be metabolized in the intestine.

• Cytochrome P450 3A4 isozyme(CYP3A4) is a major metabolic enzyme in intestinal epithelial cells. • This isozyme metabolizes diverse compound structures.

• Intestinal metabolism is considered part of “first-pass metabolism,” which is the initial metabolism of drugs before they reach systemic circulation.

• CYP3A4 has similar substrate specificity to Pgp.

• The two seem to work in concert; Pgp reduces the intracellular concen-tration of drug in the epithelial cells, which allows CYP3A4 to catalyze drug oxida-tion in an efficient manner, without being saturated

3.4.4 Enzymatic Hydrolysis in the Intes-tine

• GI enzymes can also catalyze drug hydrolysis.• Drugs can be hydrolyzed before they reach the bilayer membrane.• Prodrugs are designed to take advantage of hydrolysis.• Compounds that have a desirable pharmacological effect, but lack sufficient solu-bility for absorption, have been modified to add a substructure that increases solu-bility in the intestine (e.g., phosphate). • The increased solubility allows the modified compound to diffuse to the cell sur-face. • The hydrolytic enzyme cleaves off this substructure, just before it reaches the bi-layer membrane. • The active drug is released and permeates through the epithelial cells to reach systemic circulation

3.4.5 Absorption Enhancement in the Intestine

ex) grinding, nanoparticle

Introduce a solubilizing functional group

ex) taurochlorate, glycocholate

ex) triacylglycerols

3.5 Barriers in the Bloodstream

3.5.1 Plasma Enzyme Hydrolysis

3.5.2 Plasma Protein Binding

3.5.3 Red Blood Cell Binding

• Plasma enzyme : cholinesterase, aldolase, lipase, dehydropeptidase, alkaline and acid phosphatase, glucuronidase, dehydrogenase, and phenol sulfatase.

• The most common reaction is hydrolysis.

1) Human serum albumin (HSA) has at least six binding sites with molecular binding speci-ficity.Two sites bind fatty acid (acidic drugs) and another binds bilirubin. Warfarin and phenylbutazone bind at one site and diazepam and ibuprofen at another.Other drugs can also bind to sites on human serum albumin.2) Basic drugs can bind to 1-Acid glycoprotein. (glycoprotein include disopyramide and ligno-caine.)This protein has one binding site. This protein can be saturated at higher drug concentrations.3) Lipoproteins occur as particles and serve the natural function of transporting cholesteroland triacylgylcerols (hydrophobic lipids). They consist of nonpolar lipids, surrounded by more po-lar lipids and protein. Binding of drug molecules involves nonspecific lipophilic interactions.

3.6 Barriers in the Liver

3.6.1 Metabolism

3.6.2 Biliary Excretion

phase I : oxidation / reductionPhase II :

3.7 Barriers in the Kidney

• The liver and kidney are the major organs of elimination for most compounds.• The primary unit of renal (kidney) elimination is the nephron.• The first stage of renal elimination is termed filtration. Approximately 10% of total renal blood flow passes through the glomerulus, a complex mesh of blood capillaries. • These present a high surface area to the Bowman’s capsule, which is connected to the urinary sys-tem. • The membranes of the Bowman’s capsule have loose junctions, which allow a high rate of paracellu-lar permeation of water, drug molecules, and other blood components but normally not proteins or cells. • Molecules can also permeate passively. • In the proximal tubule, some drug molecules can be actively secreted from the bloodstream by transporters. • Much of the water (99%) and some of the drug molecules are reabsorbed by passive diffusion.

말단세뇨관

신동맥

사구체

근위세뇨관

신정맥

http://www.unckidneycenter.org/kid-neyhealthlibrary/glomerulardis-ease.html

3.9 Tissue Distribution

• lipophilic compounds tend to accumulate in adipose tissues. • Acidic compounds accumulate in muscle, which has a pH of approximately 6.

3.10 Consequences of Chirality on Barriers and Properties

3.11 Overview of in vivo Barriers to drug delivery to the target.