Abstract
Clonidine is a centrally acting, α-2 adrenergic agonist used for the treatment of hypertension during pregnancy. The metabolic pathways of clonidine are poorly understood, and the quantitative contribution of specific human cytochrome P450 (P450) isoforms has not been systematically assessed. In this study, 17 cDNA-expressed P450 enzymes, in addition to pooled human liver microsomes, were evaluated for clonidine 4-hydroxylation activity in vitro. Five P450 enzymes—CYP2D6, 1A2, 3A4, 1A1, and 3A5—catalyzed measurable formation of 4-hydroxyclonidine. Selective inhibition studies in human liver microsomes confirmed that these isoforms are jointly responsible for 4-hydroxylation of clonidine in vitro, and CYP2D6 accounted for approximately two-thirds of the activity. The major role of CYP2D6 in clonidine metabolism might explain the increase in its nonrenal clearance during pregnancy.
Footnotes
This work was supported by the National Institutes of Health Eunice Kennedy Shriver National Institute of Child Health and Human Development [Grant U10-HD047892] (in support of the Obstetric-Fetal Pharmacology Research Unit Network).
The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health and Human Development or the National Institutes of Health.
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
doi:10.1124/dmd.110.033878.
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ABBREVIATIONS:
- P450
- cytochrome P450
- HLM
- human liver microsomes
- PCR
- polymerase chain reaction
- %CV
- percent coefficient of variance
- PM
- poor metabolizer
- EM
- extensive metabolizer.
- Received April 7, 2010.
- Accepted June 22, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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