Ji-Young Park, MD

Dept. of Clinical Pharmacology & Toxicology

Anam Hospital, Korea University College of Medicine

* = Pharmacokinetics (약동학) + Pharmacodynamics (약력학)

Absorption (흡수)

Distribution (분포)

Metabolism (대사)

Excretion (소실)

Receptor at action site

second messengers

(ATP, GTP…)

clinical effect

(BP ….)

3

PK

PD

ADME Absorption – the process of getting drug into the body (not necessarily the systemic circ

ulation)

Distribution – the processes of distribution into and out of the tissues

Metabolism – the processes that change the drug to another molecule

Excretion – the processes that remove drug from the body

Collectively, these processes are referred to as ADME

Tx. failure

Toxicity

치료반응의 예측

Use of blood concentrations of drug in PK

study

5

작용부위(ACTION SITE)

“수용체(RCEPTOR)” bound free

유리약물(Free drug) 흡수(ABSORTPION) 소실(EXCRETION)

조직 (TISSUE RESERVOIR)

free bound

대사 (BIOTRANSFORMATION)

bound drug 대사물(metabolite)

SYSTEMIC CIRCULATION

Drug

Dose Concentration

in plasma

Concentration

at effect site Pharmacological

Effect

Analytical

method Hard to

measure

(invasive)

Hard to

measure

(outcome)

Surrogate

marker

7

Plasma Concentration (ng/mL) versus Time (h) PK parameters F (Bioavailability)

Cmax

Tmax

AUCall (AUClast), AUCinf

Clearance

Volume of distribution (Vd)

Half-life

Ke (Elimination Constant)

MRT (Mean Residence Time)

*Absorption Oral absorption and bioavailability

Elevation of progesterone

Reduced gastric emptying time

Reduced intestinal motility

Cmax의 감소와 Tmax의 증가 minimal effect on bioavailability

Increase in gastric pH

ionization of weak acid reduction in absorption of weak acid drugs

More critical problems: nausea and vomiting associated with pregnancy

* Distribution Expansion of intravascular (plasma volume) and extra vascular (breasts, uterus, peripheral edema) water content.

* 임산부의 1/3에서 edema를 경험 (ECF가 최대 8L까지 증가)

Total body water의 증가

hydrophilc drug에 대한 Vd의 증가 apparent dilution of drug concentrations

(compensation by changes in protein biding)

Volume of distribution plasma volume (임신 6-8주부터 증가 32-34주까지) (약 1.2-1.3 L 증가) non-pregnant women에 비해 40% 증가 cardiac output의 증가와 관련

Plasma albumin 농도 감소 dilutional effect of plasma volume

원인: albumin 합성의 감소 또는 clearance의 증가 Increased in drug effect by elevation of free forms

α1-acid glycoprotein; relatively unchanged during pregnancy

Protein binding의 감소: free form 증가

Increase in body fat (약 4kg 증가) lipophilc drug에 대한 Vd의 증가

임상적 의의는 거의 없음.

Partially compensated respiratory alkalosis: protein binding에 영향

Organ blood flow의 증가

uterus, kidney, skin, and mammary gland

with compensatory decrease in skeletal muscle blood flow

Hepatic blood blow는 영향이 거의 없음 (but lower as a percentage of cardiac output

* Metabolism 대체로 약물 대사능은 증가함

몇몇 hepatic cytochrome P450 enzyme induction

원인: estrogen/progesterone 약물대사의 증가

Cholinesterase activity: 임신시 감소

CYP2D6 activity: increased in pregnancy

* Nelfinavir & active metabolite (M8) Pharmacokinetics

Heeswiik et al. CPT 2004

pregnancy (open circles)

Post partum (solid circles)

In conclusion, there is an increased prevalence of

subtherapeutic plasma nelfinavir concentrations

during pregnancy. In addition, concentrations of

the active metabolite M8 are significantly reduced.

* Caffeine Clearance – CYP1A2

Aldridge A, et al. Semin Perinatol 1981;5:310-4.

0

10

20

30

40

50

60

70

80

90

0 10 20

WEEKS POSTPARTUM

0

10

20

30

40

50

60

70

80

90

10 15 20 25 30 35 40

WEEKS OF PREGNANCY

CL

EA

RA

NC

E (

mL

/kg

x h

r)

BIRTH

* Lamotrigine clearance in pregnancy

Tran TA, et al. Neurology 2002; 59: 251-55.

Phase II biotransformation by glucuronidation

Increased clearance in second and third trimesters ( > 65%)

May require dose adjustment

Rapid decrease in clearance in the first two weeks postpartum

* Elimination

Renal blood flow: 임신시 60%증가 (최대 2배까지 증가하기도)

Glomerular filtration rate: 임신시 50% 증가

Unchanged form으로 제거되는 약물 (e.g. penicillin, digoxin)의 배설증가

80

100

120

140

160

180

200

15-18 wks 25-28 wks 35-38 wks 8-12 wks

CL

EA

RA

NC

E (

mL

/min

)

PREGNANT POSTPARTUM

CLCr

sitting

CLCr 24°

CLINULIN sitting

Davison JM, Hytten FE. Br J Obstet Gynaecol Br Commonw 1974;81:588-95.

* Theophylline clearance during pregnancy and postpartum

0

0.2

0.4

0.6

0.8

1

1.2

24-36 wks 36-38 wks 6-8 wks > 6 mo

CL

EA

RA

NC

E (

mL

/min

x k

g) CLE

CLNR

CLR

PREGNANT POSTPARTUM

Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.

* Placental transport

*Passive diffusion

*P-glycoprotein expressed on trophoblastic cells of placenta

*Active transport of P-gp substrates back to the mother

*Pore system

*Endocytosis

MPERIPHERAL

MCENTRAL

FETUS

DOSE

CL E

FETAL

EXCRETION

+

METABOLISM

Placenta

* P-gp deficient mdr1a and mdr1b (-/-) CF-1 mice

pronounced increase in fetal exposure to P-gp substrates

ABC (ATP-binding cassette) drug efflux transporter

syncytiotraophoblast

Schematic representation of the role of the major placental efflux drug transporters in

syncytiotrophoblast layer.

BCRP: Breast cancer-resistance protein; MRP: Multi-drug resistance-associated protein; P-gp: P-

glycoprotein

* ABCG2 (BCRP) transporter

Kobayashi et al. DMD 2005

Placental BCRP mRNA (left) and protein (right)

expression levels in various BCRP haplotypes

Western blot analysis of BCRP expression in

human placentas

* Effect of gestational age

*Toxic insult by xenobiotics greater danger to fetus in early

pregnancy

*BCRP protein ↑ but not mRNA level with advancing gestational age

* Effect of maternal age

* Effect of genetic polymorphism

* Effect of hormones

*Progesterone and estrogen↓

* leflunomide case

Mean plasma concentrations of A771726 after a single dose of 20 mg

leflunomide orally according to ABCG2 c.421C>A (a) and c.34G>A (b) genotypes

* Teratogens act with specificity

* Teratogens demonstrate a dose-response relationship

*PK aspect:

* drug level modulation: ADME

* role of transporter: modulation of transporter activity * inhibitor or inducer

* genetic problems.