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 ….) 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 3 치료반응의 예측 Toxicity Tx. failure Use of blood concentrations of drug in PK study 작용부위(ACTION SITE) “수용체(RCEPTOR)” bound free 조직 free (TISSUE RESERVOIR) bound SYSTEMIC CIRCULATION 유리약물(Free drug) 흡수(ABSORTPION) bound drug 대사 소실(EXCRETION) 대사물(metabolite) (BIOTRANSFORMATION) 5 Drug Dose Concentration in plasma Analytical method Concentration at effect site Pharmacological Effect Hard to measure (outcome) Hard to measure (invasive) Surrogate marker PK parameters F (Bioavailability) Cmax Tmax AUCall (AUClast), AUCinf Clearance Volume of distribution (Vd) Half-life Ke (Elimination Constant) MRT (Mean Residence Time) Plasma Concentration (ng/mL) versus Time (h) 7 *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 women 에 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 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. Heeswiik et al. CPT 2004 CLEARANCE (mL/kg x hr) * Caffeine Clearance – CYP1A2 90 90 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 BIRTH 0 0 10 15 20 25 30 WEEKS OF PREGNANCY 35 400 10 20 WEEKS POSTPARTUM Aldridge A, et al. Semin Perinatol 1981;5:310-4. * Lamotrigine clearance in pregnancy     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 Tran TA, et al. Neurology 2002; 59: 251-55. * 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 CLEARANCE (mL/min) 200 CLINULIN sitting 180 CLCr sitting 160 140 120 CLCr 24° 100 80 15-18 wks 25-28 wks PREGNANT 35-38 wks 8-12 wks POSTPARTUM Davison JM, Hytten FE. Br J Obstet Gynaecol Br Commonw 1974;81:588-95. * Theophylline clearance during pregnancy and postpartum CLEARANCE (mL/min x kg) 1.2 1 0.8 CLE CLNR 0.6 0.4 CLR 0.2 0 24-36 wks PREGNANT 36-38 wks 6-8 wks > 6 mo 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 DOSE Placenta MPERIPHERAL MCENTRAL CL E FETUS FETAL EXCRETION + METABOLISM * 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: Pglycoprotein * ABCG2 (BCRP) transporter Western blot analysis of BCRP expression in human placentas Placental BCRP mRNA (left) and protein (right) expression levels in various BCRP haplotypes Kobayashi et al. DMD 2005 * 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.