RT Journal Article SR Electronic T1 CYP2D6 CATALYZES 5-HYDROXYLATION OF 1-(2-PYRIMIDINYL)-PIPERAZINE, AN ACTIVE METABOLITE OF SEVERAL PSYCHOACTIVE DRUGS, IN HUMAN LIVER MICROSOMES JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 203 OP 208 DO 10.1124/dmd.104.001198 VO 33 IS 2 A1 Nirmala Raghavan A1 Donglu Zhang A1 Mingshe Zhu A1 Jianing Zeng A1 Lisa Christopher YR 2005 UL http://dmd.aspetjournals.org/content/33/2/203.abstract AB 1-(2-Pyrimidinyl)-piperazine (1-PP) is an active metabolite of several psychoactive drugs including buspirone. 1-PP is also the major metabolite in the human circulation and in rat brains following oral administration of buspirone. This study was conducted to identify the enzyme responsible for the metabolic conversion of 1-PP to 5-hydroxy-1-(2-pyrimidinyl)-piperazine (HO-1-PP) in human liver microsomes (HLMs). The product HO-1-PP was quantified by a validated liquid chromatography-tandem mass spectrometry method. In the presence of NADPH, 1-PP (100 μM) was incubated separately with human cDNA-expressed cytochrome P450 isozymes (including CYP2D6, 3A4, 1A2, 2A6, 2C9, 2C19, 2E1, and 2B6) at 37°C. CYP2D6 catalyzed the formation of HO-1-PP from 1-PP. This catalytic activity was >95% inhibited by quinidine, a CYP2D6 inhibitor. HO-1-PP formation rates correlated well with the bufuralol 1-hydroxylase (CYP2D6) activities of individual HLMs. The formation of HO-1-PP followed a Michaelis-Menten kinetics with a Km of 171 μM and Vmax of 313 pmol/min · mg protein in HLMs. Collectively, these results indicate that polymorphic CYP2D6 is responsible for the conversion of 1-PP to HO-1-PP. The American Society for Pharmacology and Experimental Therapeutics