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Rapid CommunicationSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Quantitative Prediction of CYP2B6 Induction by Estradiol During Pregnancy: Potential Explanation for Increased Methadone Clearance During Pregnancy

Leslie J Dickmann and Nina Isoherranen
Drug Metabolism and Disposition February 2013, 41 (2) 270-274; DOI: https://doi.org/10.1124/dmd.112.047118
Leslie J Dickmann
Department of Pharmacokinetics and Drug Metabolism, Amgen (L.J.D.), and Department of Pharmaceutics, School of Pharmacy, University of Washington (N.I.), Seattle, Washington
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Nina Isoherranen
Department of Pharmacokinetics and Drug Metabolism, Amgen (L.J.D.), and Department of Pharmaceutics, School of Pharmacy, University of Washington (N.I.), Seattle, Washington
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Abstract

There is considerable evidence that pregnancy changes the disposition of drugs in an enzyme- and gestational stage–specific manner. On the basis of probe drug studies, the activity of CYP3A4 and CYP2D6 increases and CYP1A2 decreases during human pregnancy. However, no studies of CYP2B6 activity during human pregnancy have been conducted. In rodent models and in HepG2 cells, CYP2B enzymes have been shown to be regulated by estradiol. Because estradiol concentrations increase by ∼50-fold during human pregnancy, it was hypothesized that the increasing estradiol concentrations during human pregnancy would result in induction of CYP2B6 activity. Hepatocytes from three female donors were treated with estradiol, and the EC50 and Emax were measured for CYP2B6 mRNA and bupropion hydroxylation activity. The measured values were used to predict the magnitude of CYP2B6 induction during human pregnancy. At 100 nM total estradiol, a concentration achievable during the third trimester of pregnancy, CYP2B6 activity was predicted to increase by 1.5–3-fold, based on increased CYP2B6 activity and mRNA. When the Emax and EC50 values were compared with those for carbamazepine and rifampin, estradiol was found to be as potent an inducer of CYP2B6 as rifampin and carbamazepine. These data suggest that, during human pregnancy, the increasing estradiol concentrations will result in increased clearance of drugs that have CYP2B6-mediated clearance pathways. This could in part explain the observed increase in methadone clearance during pregnancy.

Footnotes

  • ↵Embedded ImageThis article has supplemental material available at dmd.aspetjournals.org.

  • dx.doi.org/10.1124/dmd.112.047118.

  • Received June 6, 2012.
  • Accepted July 19, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Rapid CommunicationSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Estradiol Induces CYP2B6

Leslie J Dickmann and Nina Isoherranen
Drug Metabolism and Disposition February 1, 2013, 41 (2) 270-274; DOI: https://doi.org/10.1124/dmd.112.047118

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Rapid CommunicationSpecial Section on Drug Metabolizing Enzymes and Transporters in Pregnancy

Estradiol Induces CYP2B6

Leslie J Dickmann and Nina Isoherranen
Drug Metabolism and Disposition February 1, 2013, 41 (2) 270-274; DOI: https://doi.org/10.1124/dmd.112.047118
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