Effect of multiple administration of orphenadrine or mono-N-desmethylorphenadrine on cytochrome P-450 catalyzed reactions in the rat.

Multiple administration (i.p.) of orphenadrine or its mono-N-demethylated metabolite, tofenacine (day 1, 20 mg/kg; day 2-5, 30 mg/kg) results in a considerable induction (50%) of the total cytochrome P-450 content. In addition, approximately 6% of the total amount of cytochrome P-450 was found to be blocked by a metabolic intermediate, formed from orphenadrine or tofenacine. Induction is apparent in enhancing the in vitro N-demethylation of aminopyrine and ethylmorphine and the p-hydroxylation of aniline. Pretreatment induced orphenadrine metabolism in vitro. The metabolism of tofenacine, however, was reduced. Probably this is due to a specific inhibition caused by the irreversible interaction of the metabolic intermediate with cytochrome P-450. In vivo, no induction of the aminopyrine metabolism (30 mg/kg, i.v.) is apparent, i.e., no change in the clearance was observed after pretreatment. This is probably due to the presence of relatively high, inhibitory concentrations of tofenacine (in the vicinity of cytochrome P-450). These results show that during chronic administration of orphenadrine or tofenacine, the in vivo disposition of concomitantly ingested compounds is determined by the influence of induction, high substrate and/or metabolite levels and complexation of cytochrome P-450. Moreover, based on these results an hypothesis is put forward in order to explain the phenomenon of product inhibition, which has been suggested to occur in man under chronic orphenadrine dosing conditions.