PT  - JOURNAL ARTICLE
AU  - Claessens, Adam J.
AU  - Risler, Linda J.
AU  - Eyal, Sara
AU  - Shen, Danny D.
AU  - Easterling, Thomas R.
AU  - Hebert, Mary F.
TI  - CYP2D6 Mediates 4-Hydroxylation of Clonidine In Vitro: Implication for Pregnancy-Induced Changes in Clonidine Clearance
AID  - 10.1124/dmd.110.033878
DP  - 2010 Sep 01
TA  - Drug Metabolism and Disposition
PG  - 1393--1396
VI  - 38
IP  - 9
4099  - http://dmd.aspetjournals.org/content/38/9/1393.short
4100  - http://dmd.aspetjournals.org/content/38/9/1393.full
SO  - Drug Metab Dispos2010 Sep 01; 38
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.