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

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 CLRenal, unbound (272 +/- 45 ml/min vs. 183 +/- 37 ml/min; P < 0.002) and digoxin CLsecretion, 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.