In vivo evaluation of the effects of altered cyclosporine metabolism on its immunosuppressive potency.

The dose-response and plasma concentration-response relationships of cyclosporine after both inducing and inhibiting its metabolism were studied in a mouse heart transplant model. The metabolism of cyclosporine was altered by coadministering phenobarbital and cimetidine as metabolism inducing and inhibiting agents, respectively. We found that phenobarbital depressed the immunosuppressive potency of cyclosporine by enhancing its metabolism resulting in lower cyclosporine blood levels. On the other hand, when cimetidine was administered concurrently with cyclosporine, the immunosuppressive effect was enhanced due to inhibition of the metabolism of cyclosporine which produced higher cyclosporine blood levels. When graft survival was evaluated relative to blood cyclosporine concentrations, however, it appeared that cimetidine had a direct negative effect on the survival of transplanted organs independent and contrary to its effect on the accumulation of cyclosporine. The immunosuppression produced by cyclosporine at these elevated blood levels was less than expected. The accrued data support the conclusion that cyclosporine and not its metabolites are primarily responsible for its immunosuppressive activity in the mouse.