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           Distri...
PK                                   PDADMEAbsorption – the process of getting drug into the body (not necessarily the sys...
치료반응의 예측      Toxicity      Tx. failure
Use of blood concentrations of drug in PKstudy          작용부위(ACTION SITE)          “수용체(RCEPTOR)”                         ...
Drug   Concentration   Concentration             PharmacologicalDose   in plasma       at effect site                Effec...
PK parameters                 Plasma Concentration (ng/mL) versus Time (h)F (Bioavailability)CmaxTmaxAUCall (AUClast), AUC...
*Absorption   Oral absorption and bioavailability     Elevation of progesterone        Reduced gastric emptying time      ...
* Distribution     Expansion of intravascular (plasma volume) and extra vascular (breasts,    uterus, peripheral edema) wa...
Partially compensated respiratory alkalosis: protein binding에 영향Organ blood flow의 증가   uterus, kidney, skin, and mammary g...
* Metabolism   대체로 약물 대사능은 증가함   몇몇 hepatic cytochrome P450 enzyme induction     원인: estrogen/progesterone  약물대사의 증가   Ch...
* Nelfinavir & active metabolite (M8) Pharmacokinetics                                                       pregnancy (op...
* Caffeine Clearance – CYP1A2                         90                                           90CLEARANCE (mL/kg x hr...
* Lamotrigine clearance in pregnancy    Phase II biotransformation by glucuronidation    Increased clearance in second a...
* Elimination  Renal blood flow: 임신시 60%증가 (최대 2배까지 증가하기도)  Glomerular filtration rate: 임신시 50% 증가  Unchanged form으로 제거되는...
* Theophylline clearance during pregnancy and postpartum                                   1.2                            ...
* Placental transport    * Passive diffusion    * P-glycoprotein expressed on trophoblastic cells of placenta    * Active ...
DOSE                         Placenta              MCENTRAL          FETUSMPERIPHERAL                                FETAL...
* P-gp deficient mdr1a and mdr1b (-/-) CF-1 mice     pronounced increase in fetal exposure to P-gp substrates  ABC (ATP-...
* ABCG2     (BCRP) transporter                                               Western blot analysis of BCRP expression in  ...
*   Effect of gestational age    * Toxic insult by xenobiotics  greater danger to fetus in early      pregnancy    * BCRP...
* leflunomide case     Mean plasma concentrations of A771726 after a single dose of 20 mg     leflunomide orally according...
* Teratogens act with specificity* Teratogens demonstrate a dose-response relationship* PK aspect:   * drug level modulati...
<마더리스크라운드> Pharmacokinetics in pregnancy
<마더리스크라운드> Pharmacokinetics in pregnancy
<마더리스크라운드> Pharmacokinetics in pregnancy
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<마더리스크라운드> Pharmacokinetics in pregnancy

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<마더리스크라운드> Pharmacokinetics in pregnancy

  1. 1. Ji-Young Park, MD Dept. of Clinical Pharmacology & ToxicologyAnam Hospital, Korea University College of Medicine
  2. 2. * = Pharmacokinetics (약동학) + Pharmacodynamics (약력학) Absorption (흡수) Receptor at action site Distribution (분포)   second messengers Metabolism (대사) (ATP, GTP…) Excretion (소실)     clinical effect (BP ….)
  3. 3. 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
  4. 4. 치료반응의 예측 Toxicity Tx. failure
  5. 5. 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
  6. 6. Drug Concentration Concentration PharmacologicalDose in plasma at effect site Effect Analytical Hard to Hard to method measure measure (outcome) (invasive) Surrogate marker
  7. 7. 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
  8. 8. *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
  9. 9. * 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.
  10. 10. 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
  11. 11. * 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
  12. 12. * 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
  13. 13. * Caffeine Clearance – CYP1A2 90 90CLEARANCE (mL/kg x hr) 80 80 70 70 60 60 50 50 40 40 30 30 20 20 10 10 0 BIRTH 0 10 15 20 25 30 35 40 0 10 20 WEEKS OF PREGNANCY WEEKS POSTPARTUM Aldridge A, et al. Semin Perinatol 1981;5:310-4.
  14. 14. * 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.
  15. 15. * 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 200 CLINULIN sitting 180 CLEARANCE (mL/min) CLCr 160 sitting 140 120 100 CLCr 24° 80 15-18 wks 25-28 wks 35-38 wks 8-12 wks PREGNANT POSTPARTUM Davison JM, Hytten FE. Br J Obstet Gynaecol Br Commonw 1974;81:588-95.
  16. 16. * Theophylline clearance during pregnancy and postpartum 1.2 CLE CLEARANCE (mL/min x kg) 1 0.8 CLNR 0.6 0.4 CLR 0.2 0 24-36 wks 36-38 wks 6-8 wks > 6 mo PREGNANT POSTPARTUM Frederiksen MC, et al. Clin Pharmacol Ther 1986;40:321-8.
  17. 17. * 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
  18. 18. DOSE Placenta MCENTRAL FETUSMPERIPHERAL FETAL EXCRETION CL E + METABOLISM
  19. 19. * 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
  20. 20. * 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
  21. 21. * 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↓
  22. 22. * 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
  23. 23. * 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.
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