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...

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Published in:Clinical pharmacology and therapeutics 2008-08, Vol.84 (2), p.248-253
Main Authors: Hebert, MF, Easterling, TR, Kirby, B, Carr, DB, Buchanan, ML, Rutherford, T, Thummel, KE, Fishbein, DP, Unadkat, JD
Format: Article
Language:English
Subjects:
Adult
Anesthetics, Intravenous - pharmacokinetics
Anti-Anxiety Agents - pharmacokinetics
Anti-Arrhythmia Agents - pharmacokinetics
Area Under Curve
ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism
Biological and medical sciences
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
Medical sciences
Midazolam - blood
Midazolam - pharmacokinetics
Midazolam - urine
Pharmacology. Drug treatments
Postpartum Period - metabolism
Pregnancy - metabolism
Pregnancy Trimester, Third - metabolism
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Summary: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/Funbound (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. Clinical Pharmacology & Therapeutics (2008); 84, 2, 248–253 doi:10.1038/clpt.2008.1
ISSN:0009-9236
1532-6535
DOI:10.1038/clpt.2008.1