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Quinney SK, Mohamed AN, Hebert MF, et al. A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2012;1:e2doi: 10.1038/psp.2012.5.
Quinney, S. K., Mohamed, A. N., Hebert, M. F., Haas, D. M., Clark, S., Umans, J. G., Caritis, S. N., & Li, L. (2012). A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics. CPT: pharmacometrics & systems pharmacology, 1e2. https://doi.org/10.1038/psp.2012.5
Quinney, S K, et al. "A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics." CPT: pharmacometrics & systems pharmacology vol. 1 (2012): e2. doi: https://doi.org/10.1038/psp.2012.5
Quinney SK, Mohamed AN, Hebert MF, Haas DM, Clark S, Umans JG, Caritis SN, Li L. A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics. CPT Pharmacometrics Syst Pharmacol. 2012 Sep 26;1:e2. doi: 10.1038/psp.2012.5. PMID: 23835882; PMCID: PMC3603475.
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CPT Pharmacometrics Syst Pharmacol. 2012 Sep 26;1:e2. doi: 10.1038/psp.2012.5.

A Semi-Mechanistic Metabolism Model of CYP3A Substrates in Pregnancy: Predicting Changes in Midazolam and Nifedipine Pharmacokinetics.

CPT: pharmacometrics & systems pharmacology

S K Quinney, A N Mohamed, M F Hebert, D M Haas, S Clark, J G Umans, S N Caritis, L Li

Affiliations

  1. 1] Department of Obstetrics and Gynecology and Department of Medicine Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA [2] Department of Obstetrics and Gynecology and Department of Medicine Division of Clinical Pharmacology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

PMID: 23835882 PMCID: PMC3603475 DOI: 10.1038/psp.2012.5

Abstract

Physiological changes in pregnancy, including changes in body composition and metabolic enzyme activity, can alter drug pharmacokinetics. A semi-mechanistic metabolism model was developed to describe the pharmacokinetics of two cytochrome P450 3A (CYP3A) substrates, midazolam and nifedipine, in obstetrics patients. The model parameters were optimized to fit the data of oral midazolam pharmacokinetics in pregnant women, by increasing CYP3A-induced hepatic metabolism 1.6-fold in the model with no change in gut wall metabolism. Fetal metabolism had a negligible effect on maternal plasma drug concentrations. Validation of the model was performed by applying changes in volume of distribution and metabolism, consistent with those observed for midazolam, to the pharmacokinetics parameters of immediate-release nifedipine in healthy volunteers. The predicted steady-state areas under the concentration-time curve (AUCs) for nifedipine were within 15% of the data observed in pregnant women undergoing treatment for preterm labor. This model predicts the pharmacokinetics of two CYP3A substrates in pregnancy, and may be applicable to other CYP3A substrates as well.CPT: Pharmacometrics & Systems Pharmacology (2012) 1, e2; doi:10.1038/psp.2012.5; advance online publication 26 September 2012.

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