Ji-Young Park, MD Dept. of Clinical Pharmacology & ToxicologyAnam Hospital, Korea University College of Medicine
* = Pharmacokinetics (약동학) + Pharmacodynamics (약력학) Absorption (흡수) Receptor at action site Distribution (분포) second messengers Metabolism (대사) (ATP, GTP…) Excretion (소실) clinical effect (BP ….)
PK PDADMEAbsorption – the process of getting drug into the body (not necessarily the systemic circulation)Distribution – the processes of distribution into and out of the tissuesMetabolism – the processes that change the drug to another moleculeExcretion – the processes that remove drug from the bodyCollectively, these processes are referred to as ADME 3
Use of blood concentrations of drug in PKstudy 작용부위(ACTION SITE) “수용체(RCEPTOR)” 조직 (TISSUE RESERVOIR) bound free free bound SYSTEMIC CIRCULATION 흡수(ABSORTPION) 유리약물(Free drug) 소실(EXCRETION) bound drug 대사물(metabolite) 대사 (BIOTRANSFORMATION) 5
Drug Concentration Concentration PharmacologicalDose in plasma at effect site Effect Analytical Hard to Hard to method measure measure (outcome) (invasive) Surrogate marker
PK parameters Plasma Concentration (ng/mL) versus Time (h)F (Bioavailability)CmaxTmaxAUCall (AUClast), AUCinfClearanceVolume of distribution (Vd)Half-lifeKe (Elimination Constant)MRT (Mean Residence Time) 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 영향Organ blood flow의 증가 uterus, kidney, skin, and mammary gland with compensatory decrease in skeletal muscle blood flowHepatic blood blow는 영향이 거의 없음 (but lower as a percentage of cardiacoutput
* 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
* 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.
* 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 syncytiotraophoblastSchematic representation of the role of the major placental efflux drug transporters insyncytiotrophoblast layer.BCRP: Breast cancer-resistance protein; MRP: Multi-drug resistance-associated protein; P-gp: P-glycoprotein
* 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.