PT  - JOURNAL ARTICLE
AU  - Hirotoshi Echizen
AU  - Michika Tanizaki
AU  - Jun Tatsuno
AU  - Kan Chiba
AU  - Teresa Berwick
AU  - Masayoshi Tani
AU  - Frank J. Gonzalez
AU  - Takashi Ishizaki
TI  - Identification of CYP3A4 as the Enzyme Involved in the Mono-<em>N</em>-Dealkylation of Disopyramide Enantiomers in Humans
DP  - 2000 Aug 01
TA  - Drug Metabolism and Disposition
PG  - 937--944
VI  - 28
IP  - 8
4099  - http://dmd.aspetjournals.org/content/28/8/937.short
4100  - http://dmd.aspetjournals.org/content/28/8/937.full
SO  - Drug Metab Dispos2000 Aug 01; 28
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