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

Clin Pharmacol Ther. 2008 Aug;84(2):248-53. doi: 10.1038/clpt.2008.1. Epub 2008 Feb 20.

Abstract

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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Adult
  • Anesthetics, Intravenous / pharmacokinetics
  • Anti-Anxiety Agents / pharmacokinetics
  • Anti-Arrhythmia Agents / pharmacokinetics
  • Area Under Curve
  • Cardiotonic Agents / pharmacokinetics
  • Creatinine / urine
  • Cytochrome P-450 CYP3A / metabolism*
  • Digoxin / blood
  • Digoxin / pharmacokinetics*
  • Digoxin / urine
  • Enzyme Inhibitors / pharmacokinetics
  • Female
  • Gas Chromatography-Mass Spectrometry
  • Genotype
  • Humans
  • Hypnotics and Sedatives / pharmacokinetics
  • Midazolam / blood
  • Midazolam / pharmacokinetics*
  • Midazolam / urine
  • Postpartum Period / metabolism*
  • Pregnancy / metabolism*
  • Pregnancy Trimester, Third / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anesthetics, Intravenous
  • Anti-Anxiety Agents
  • Anti-Arrhythmia Agents
  • Cardiotonic Agents
  • Enzyme Inhibitors
  • Hypnotics and Sedatives
  • Digoxin
  • Creatinine
  • Cytochrome P-450 CYP3A
  • Midazolam