Effect of Drug Pre-treatment on the Oxidative Metabolism of Cimetidine and Metiamide.
The effect of pretreatment with classical enzyme inducers and inhibitors on the oxidative metabolism of cimetidine and metiamide was studied in white albino male rats using thin layer chromatography (t.l.c.) and UV-spectrophotometric assay. Phenobarbitone sodium and alcohol significantly induced the sulphoxidation of both cimetidine and metiamide. Pregnenolone induced the sulphoxidation of cimetidine but not that of metiamide. 5-Hydroxymethyl metiamide formation was significantly induced by phenobarbitone, anthracene and pregnenolone but only phenobarbitone significantly induced 5-methyl hydroxylation of cimetidine. Methimazole but not metyrapone had significant inhibitory effect on sulphoxidation of cimetidine but both drugs had little or no effect on the sulphoxidation of metiamide. 5-Hydroxymethyl cimetidine formation was drastically inhibited by metyrapone and methimazole but the former had no significant effect on the 5-hydroxymethyl metiamide formation. The results of this study suggest that the metabolism of cimetidine and metiamide are mediated by at least three different oxidative mechanisms. Both the S-oxidation and 5-methylhydroxylation mechanisms differ in both cimetidine and metiamide. The data for sulphoxidation of cimetidine strongly suggest the involvement of FAD-mediated mechanism while the 5-methylhydroxylation is most likely via cytochrome p-450. The possible contribution of physicochemical properties to the differences in the biotransformation of cimetidine and metiamide is also discussed.