RT Journal Article SR Electronic T1 Identification of CYP3A4 as the Enzyme Involved in the Mono-N-Dealkylation of Disopyramide Enantiomers in Humans JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 937 OP 944 VO 28 IS 8 A1 Hirotoshi Echizen A1 Michika Tanizaki A1 Jun Tatsuno A1 Kan Chiba A1 Teresa Berwick A1 Masayoshi Tani A1 Frank J. Gonzalez A1 Takashi Ishizaki YR 2000 UL http://dmd.aspetjournals.org/content/28/8/937.abstract AB To identify which cytochrome P-450 (CYP) isoform(s) are involved in the major pathway of disopyramide (DP) enantiomers metabolism in humans, the in vitro formation of mono-N-desalkyldisopyramide from each DP enantiomer was studied with human liver microsomes and nine recombinant human CYPs. Substrate inhibition showed that SKF 525A and troleandomycin potently suppressed the metabolism of both DP enantiomers with IC50values for R(−)- and S(+)-DP of <7.3 and <18.9 μM, respectively. In contrast, only weak inhibitory effects (i.e., IC50 > 100 μM) were observed for five other representative CYP isoform substrates [i.e., phenacetin (CYP1A1/2), sparteine (CYP2D6), tolbutamide (CYP2C9),S-mephenytoin (CYP2C19), andp-nitrophenol (CYP2E1)]. Significant correlations (P < .01, r = 0.91) were found between the activities of 11 different human liver microsomes for mono-N-dealkylation of both DP enantiomers and that of 6β-hydroxylation of testosterone. Conversely, no significant correlations were observed between the catalytic activities for DP enantiomers and those for the O-deethylation of phenacetin, 2-hydroxylation of desipramine, hydroxylation of tolbutamide, and 4′-hydroxylation of S-mephenytoin. Further evidence for involvement of CYP3A P450s was revealed by an anti-human CYP3A serum that inhibited the mono-N-dealkylation of both DP enantiomers and 6β-hydroxylation of testosterone almost completely (i.e., >90%), whereas it only weakly inhibited (i.e., <15%) CYP1A1/2- or 2C19-mediated reactions. Finally, the recombinant human CYP3A3 and 3A4 showed much greater catalytic activities than seven other isoforms examined (i.e., CYP1A2, 2A6, 2B6, 2C9, 2D6, 2E1, and 3A5) for both DP enantiomers. In conclusion, the metabolism of both DP enantiomers in humans would primarily be catalyzed by CYP3A4, implying that DP may have an interaction potential with other CYP3A substrates and/or inhibitors. The American Society for Pharmacology and Experimental Therapeutics