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 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.
Hebert
M F
MF
Department of Pharmacy, University of Washington, Seattle, Washington, USA. mhebert@u.washington.edu
Easterling
T R
TR
Kirby
B
B
Carr
D B
DB
Buchanan
M L
ML
Rutherford
T
T
Thummel
K E
KE
Fishbein
D P
DP
Unadkat
J D
JD
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000328:Adult; D018686:Anesthetics, Intravenous / Q000493:pharmacokinetics; D014151:Anti-Anxiety Agents / Q000493:pharmacokinetics; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics; D019540:Area Under Curve; D002316:Cardiotonic Agents / Q000493:pharmacokinetics; D003404:Creatinine / Q000652:urine; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D004077:Digoxin / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005838:Genotype; D006801:Humans; D006993:Hypnotics and Sedatives / Q000493:pharmacokinetics; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D049590:Postpartum Period / Q000378:metabolism*; D011247:Pregnancy / Q000378:metabolism*; D011263:Pregnancy Trimester, Third / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018686:Anesthetics, Intravenous; D014151:Anti-Anxiety Agents; D000889:Anti-Arrhythmia Agents; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D006993:Hypnotics and Sedatives; D004077:Digoxin; D003404:Creatinine; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam