Role of specific cytochrome P450 enzymes in the N-oxidation of the antiarrhythmic agent mexiletine

Abstract

1. Mexiletine is extensively metabolized in man by C- and N-oxidation and the aim of the present study was to characterize major cytochrome P450 enzyme(s) involved in the formation of N -hydroxymexiletine. 2. Incubations with genetically engineered microsomes indicated that the formation rate of N -hydroxymexiletine was highest in the presence of microsomes expressing high levels of either CYP1A2 or CYP2E1 and the formation of N -hydroxymexiletine by human liver microsomes was inhibited about 40% by antibodies directed against CYP1A1/1A2 or CYP2E1. Additional incubations demonstrated that formation of N -hydroxymexiletine was decreased 47 and 51% by furafylline, 40 µm and 120 µm, respectively, and decreased 55 and 67% by α -naphthoflavone, 1 µm and 3 µm, respectively (all p < 0.05 versus control). 3. The formation rate of N -hydroxymexiletine in human liver microsomes was highly correlated with CYP2B6 (RS -mexiletine, r = 0.7827; R - (−) -enantiomer, r = 0.7034; S -(+)-enantiomer, r = 0.7495), CYP2E1 (S -(+)-enantiomer, r = 0.7057) and CYP1A2 (RS -mexiletine, r = 0.5334; S -(+)-enantiomer, r = 0.6035). 4. In conclusion, we have demonstrated that CYP1A2 is a major human cytochrome P450 enzyme involved in the formation of N -hydroxymexiletine. However, other cytochrome P450 enzymes (CYP2E1 and CYP2B6) also appear to play a role in the N-oxidation of this drug.