Document Detail

Quantitative prediction of CYP2B6 induction by estradiol during pregnancy: potential explanation for increased methadone clearance during pregnancy.
MedLine Citation:
PMID:  22815312     Owner:  NLM     Status:  MEDLINE    
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 EC(50) and E(max) 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 E(max) and EC(50) 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.
Leslie J Dickmann; Nina Isoherranen
Publication Detail:
Type:  Comparative Study; Journal Article     Date:  2012-07-19
Journal Detail:
Title:  Drug metabolism and disposition: the biological fate of chemicals     Volume:  41     ISSN:  1521-009X     ISO Abbreviation:  Drug Metab. Dispos.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-01-18     Completed Date:  2013-07-12     Revised Date:  2014-01-07    
Medline Journal Info:
Nlm Unique ID:  9421550     Medline TA:  Drug Metab Dispos     Country:  United States    
Other Details:
Languages:  eng     Pagination:  270-4     Citation Subset:  IM    
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MeSH Terms
Analgesics, Opioid / metabolism*
Aryl Hydrocarbon Hydroxylases / biosynthesis*,  genetics
Bupropion / metabolism
Carbamazepine / pharmacology
Cells, Cultured
Dose-Response Relationship, Drug
Enzyme Induction
Estradiol / pharmacology*
Hepatocytes / drug effects*,  enzymology
Metabolic Clearance Rate
Methadone / metabolism*
Oxidoreductases, N-Demethylating / biosynthesis*,  genetics
Primary Cell Culture
RNA, Messenger / biosynthesis
Rifampin / pharmacology
Substrate Specificity
Reg. No./Substance:
0/Analgesics, Opioid; 0/RNA, Messenger; 01ZG3TPX31/Bupropion; 33CM23913M/Carbamazepine; 4TI98Z838E/Estradiol; EC 1.14.13.-/cytochrome P-450 CYP2B6; EC Hydrocarbon Hydroxylases; EC 1.5.-/Oxidoreductases, N-Demethylating; UC6VBE7V1Z/Methadone; VJT6J7R4TR/Rifampin

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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