RT Journal Article
SR Electronic
T1 CYP2D6 Mediates 4-Hydroxylation of Clonidine In Vitro: Implication for Pregnancy-Induced Changes in Clonidine Clearance
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1393
OP 1396
DO 10.1124/dmd.110.033878
VO 38
IS 9
A1 Adam J. Claessens
A1 Linda J. Risler
A1 Sara Eyal
A1 Danny D. Shen
A1 Thomas R. Easterling
A1 Mary F. Hebert
YR 2010
UL http://dmd.aspetjournals.org/content/38/9/1393.abstract
AB 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.