1. ¹Department of Pharmacy, University of Washington, Seattle, Washington, USA
2. ²Department of Obstetrics and Gynecology, University of Washington, Seattle, Washington, USA
3. ³Department of Pharmaceutics, University of Washington, Seattle, Washington, USA
4. ⁴Division of Cardiology, University of Washington, Seattle, Washington, USA

Correspondence: MF Hebert, (mhebert@u.washington.edu); JD Unadkat, (jash@u.washington.edu)

Received 23 October 2007; Accepted 18 December 2007; Published online 20 February 2008.

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.