Premium
Effects of Pregnancy on CYP3A and P‐glycoprotein Activities as Measured by Disposition of Midazolam and Digoxin: A University of Washington Specialized Center of Research Study
Author(s) -
Hebert MF,
Easterling TR,
Kirby B,
Carr DB,
Buchanan ML,
Rutherford T,
Thummel KE,
Fishbein DP,
Unadkat JD
Publication year - 2008
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2008.1
Subject(s) - digoxin , midazolam , cyp3a , pregnancy , gestation , disposition , pharmacokinetics , urine , medicine , endocrinology , chemistry , pharmacology , metabolism , psychology , biology , heart failure , social psychology , cytochrome p450 , sedation , genetics
The objectives of the study were to evaluate the effects of pregnancy on CYP3A and P‐glycoprotein (P‐gp) activities, as measured by disposition of midazolam and digoxin, respectively. Thirteen women received digoxin (0.25 mg p.o.) and midazolam (2 mg p.o.) in random order, separated by 1–2 weeks at 28–32 weeks gestation, and the same order was repeated at 6–10 weeks postpartum. Plasma and urine concentrations were determined by liquid chromatography–mass spectrometry and analyzed by noncompartmental methods. Midazolam CL/F unbound (593 ± 237 l/min vs. 345 ± 103 l/min; P = 0.007), digoxin CL Renal, unbound (272 ± 45 ml/min vs. 183 ± 37 ml/min; P < 0.002) and digoxin CL secretion , unbound (109 ± 34 ml/min vs. 58 ± 22 ml/min; P < 0.002) were higher during pregnancy than postpartum. These data are consistent with increased hepatic and/or intestinal CYP3A and renal P‐gp activities during pregnancy. Clinical Pharmacology & Therapeutics (2008); 84 , 2, 248–253 doi: 10.1038/clpt.2008.1