RT Journal Article SR Electronic T1 (+)-N-3-Benzyl-Nirvanol and (−)-N-3-Benzyl-Phenobarbital: New Potent and Selective in Vitro Inhibitors of CYP2C19 JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 235 OP 239 DO 10.1124/dmd.30.3.235 VO 30 IS 3 A1 Suzuki, Hisashi A1 Kneller, M. Byron A1 Haining, Robert L. A1 Trager, William F. A1 Rettie, Allan E. YR 2002 UL http://dmd.aspetjournals.org/content/30/3/235.abstract AB Highly potent and selective CYP2C19 inhibitors are not currently available. In the present study, N-3-benzyl derivatives of nirvanol and phenobarbital were synthesized, their respective (+)- and (−)-enantiomers resolved chromatographically, and inhibitor potencies determined for these compounds toward CYP2C19 and other human liver cytochromes P450 (P450s). (−)-N-3-Benzyl-phenobarbital and (+)-N-3-benzyl-nirvanol were found to be highly potent, competitive inhibitors of recombinant CYP2C19, exhibitingKi values of 79 and 250 nM, respectively, whereas their antipodes were 20- to 60-fold less potent. In human liver preparations, (−)-N-3-benzyl-phenobarbital and (+)-N-3-benzyl-nirvanol inhibited (S)-mephenytoin 4′-hydroxylase activity, a marker for native microsomal CYP2C19, with Ki values ranging from 71 to 94 nM and 210 to 280 nM, respectively. At single substrate concentrations of 0.3 μM [(−)-N-3-benzyl-phenobarbital] and 1 μM [(+)-N-3-benzyl-nirvanol] that were used to examine inhibition of a panel of cDNA-expressed P450 isoforms, neither CYP1A2, 2A6, 2C8, 2C9, 2D6, 2E1, nor 3A4 activities were decreased by greater than 16%. In contrast, CYP2C19 activity was inhibited ∼80% under these conditions. Therefore, (+)-N-3-benzyl-nirvanol and (−)-N-3-benzyl-phenobarbital represent new, highly potent and selective inhibitors of CYP2C19 that are likely to prove generally useful for screening purposes during early phases of drug metabolism studies with new chemical entities. The American Society for Pharmacology and Experimental Therapeutics