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0090-9556/04/3206-584-586$20.00
DMD 32:584-586, 2004

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SHORT COMMUNICATION

VALIDATION OF (-)-N-3-BENZYL-PHENOBARBITAL AS A SELECTIVE INHIBITOR OF CYP2C19 IN HUMAN LIVER MICROSOMES

Xiaoxin Cai, Regina W. Wang, Richard W. Edom, David C. Evans, Magang Shou, A. David Rodrigues, Wensheng Liu, Dennis C. Dean, and Thomas A. Baillie

Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey (X.C., R.W.W., R.W.E., D.C.E., W.L., D.C.D.) and West Point, Pennsylvania (M.S., A.D.R., T.A.B.)

(-)-N-3-Benzyl-phenobarbital (NBPB) was reported to be a potent and selective inhibitor of CYP2C19. To validate the selectivity of NBPB toward CYP2C19 in human liver microsomes, the inhibitory effects on major cytochrome P450 isoform-specific reactions were evaluated in the present study. In human liver microsomes, NBPB showed potent competitive inhibition on CYP2C19-mediated S-mephenytoin 4'-hydroxylation with an IC50 value of 0.25 µM and Ki value of 0.12 µM, whereas weak inhibition was observed for CYP1A2-, CYP2A6-, CYP2B6-, CYP2C8-, CYP2C9-, CYP2D6-, and CYP3A4-mediated reactions with IC50 values >100, >100, 62, 34, 19, >100, and 89 µM, respectively. Importantly, its selectivity toward CYP2C19 among the CYP2C subfamily was demonstrated. Therefore, NBPB can be used as a potent and selective inhibitor to establish the relative contribution of CYP2C19 for in vitro reaction phenotyping studies. This compound can also serve as a positive control inhibitor of CYP2C19 for routine screening of P450 reversible inhibition when human liver microsomes are used as the enzyme source.

Address correspondence to: Regina W. Wang, Department of Drug Metabolism, RY80-D100, Merck Research Laboratories, P.O. Box 2000, Rahway, New Jersey 07065. E-mail: regina_wang{at}merck.com




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