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Drug Metabolism and Disposition Fast Forward
First published on October 26, 2004; DOI: 10.1124/dmd.104.001198

0090-9556/05/3302-203-208$20.00
DMD 33:203-208, 2005

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SHORT COMMUNICATION

CYP2D6 CATALYZES 5-HYDROXYLATION OF 1-(2-PYRIMIDINYL)-PIPERAZINE, AN ACTIVE METABOLITE OF SEVERAL PSYCHOACTIVE DRUGS, IN HUMAN LIVER MICROSOMES

Nirmala Raghavan, Donglu Zhang, Mingshe Zhu, Jianing Zeng, and Lisa Christopher

Pharmaceutical Candidate Optimization, Pharmaceutical Research Institute, Bristol-Myers Squibb, Princeton, New Jersey

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.

Address correspondence to: Dr. Donglu Zhang, Pharmaceutical Candidate Optimization, P.O. Box 4000, Bristol-Myers Squibb, Princeton, NJ 08543. E-mail: Donglu.Zhang{at}BMS.com






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