Placental transfer i· Pharmacogenomics 00 Polymorphisms of Cyp isoenzymes and p- glycoproteins Poor maternal metabolizers increase fetal drug o000oc0= exposure Placenta genetic characteristics are the fetus KENTUCKY College of Pharmacy
Placental Transfer • Pharmacogenomics – Polymorphisms of CYP isoenzymes and Pglycoproteins – Poor maternal metabolizers increase fetal drug exposure – Placenta genetic characteristics are the fetus’
Eab Example ABCB1 gene codes for P-glycoprotein 0:.. Polymorphism in exon 26 is C3435T 00 TT individuals have transport activity and T serum concentrations o000oc0= Maternal Effect on fetal exposure genotype (placental) CC or ct CC or ct Most commonly expected genotype representing normal transport of drugs TT CC or ct No effect or some increase CC or ct TT TT Increased exposure Increased exposure relative to other genotypes KENTUCKY De Vane CL, et al. J Psychopharmacol 2006: 20, S54-9 College of Pharmacy
Example • ABCB1 gene codes for P-glycoprotein • Polymorphism in exon 26 is C3435T • TT individuals have ↓ transport activity and ↑ serum concentrations Maternal genotype Fetal (placental) Effect on fetal exposure CC or CT CC or CT Most commonly expected genotype representing normal transport of drugs TT CC or CT No effect or some increase CC or CT TT Increased exposure TT TT Increased exposure relative to other genotypes DeVane CL, et al. J Psychopharmacol 2006;20, S54-9
Fetal outcome a. Factors affecting fetal outcome 6 RE:,-Stage of development at time of insult I Timing Potential Effect Blastogenesis(0-15 days) all or nothing Organogenesis(15-56 days) Structural abnomalities o000oc0= Ex: chemo, lithium thalidomide. certain aeds E. Fetal Period(56-birth) Growth retardation CNs abnormalities, death Concentration of the drug or offending chemical ①○×① g治fes. Drugs in pregnancy and lactation.005×i×ik KENTUCKY Wells BG. Pregnancy and lactation. 2003; (5 300-10 College of Pharmacy
Fetal Outcome • Factors affecting fetal outcome – Stage of development at time of insult – Concentration of the drug or offending chemical Yaffe SJ. Drugs in pregnancy and lactation. 2005;7: xiii-xix. Wells BG. Pregnancy and lactation. 2003;(5)300-10. Timing Potential Effect Blastogenesis (0-15 days) “all or nothing” Organogenesis (15-56 days) Structural abnomalities Ex: chemo, lithium, thalidomide, certain AEDs Fetal Period (56- birth) Growth retardation, CNS abnormalities, death
Fetal Development -age of embryo (in weeks fetal period in weeks) 6 20-36 indicates common sate of action of teratogen zygote 6 bil CNS …8) o000oc0= wer Imhs prenatal death major congenital anomalies fred Weeks 0-13-1st trimester Weeks 14-26-2nd trimester Weeks 26-40-3rd trimester KENTUCKY College of Pharmacy
Fetal Development Weeks 0-13 – 1 st trimester Weeks 14-26 – 2 nd trimester Weeks 26-40 – 3 rd trimester
e Determinants of Teratogenicity oS. Animal studies-extrapolated to humans not always valid Rt. Case reports-may have occurred by chance 当2· Epidemiological studies Case-control - recall bias may be a problem Cohort studies-expensive and need large numbers Pregnancy registries- voluntary reporting KENTUCKY College of Pharmacy
Determinants of Teratogenicity • Animal studies - extrapolated to humans not always valid • Case reports – may have occurred by chance • Epidemiological studies – Case-control – recall bias may be a problem – Cohort studies – expensive and need large numbers • Pregnancy registries – voluntary reporting