title: CYP2D6 mediates 4-hydroxylation of clonidine in vitro: implication for pregnancy-induced changes in clonidine clearance.
abstract: Clonidine is a centrally acting, alpha-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.
authors.affiliation: Department of Pharmacy, University of Washington Health Sciences Center, 1959 NE Pacific Street, Seattle, WA 98195-7630, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Claessens
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Risler
authors.forename: Sara
authors.initials: S
authors.lastname: Eyal
authors.forename: Danny D
authors.initials: DD
authors.lastname: Shen
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Easterling
authors.forename: Mary F
authors.initials: MF
authors.lastname: Hebert
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000493:pharmacokinetics* / Q000494:pharmacology; D002853:Chromatography, Liquid; D003000:Clonidine / Q000493:pharmacokinetics* / Q000494:pharmacology; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D005260:Female; D006801:Humans; D006900:Hydroxylation; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D011247:Pregnancy
chemical_list: D000316:Adrenergic alpha-Agonists; D019389:Cytochrome P-450 CYP2D6; D003000:Clonidine