Species differences in the hepatic and intestinal metabolism of cyclosporine

1. Cyclosporin A (cyclosporine, CSA) is an immunosuppressive drug with a na rrow therapeutic index. In the present study the metabolism of CSA was inve stigated in the liver and small intestinal microsomes obtained from rat, ha mster, rabbit, dog, baboon and man by measuring the disappearance of CSA an d the formation of the principal metabolites of CSA, namely hydroxylated an d N-demethylated CSA. 2. CSA was metabolized at a very slow rate (2-8 % metabolism in 30 min) in rat liver microsomes whereas microsomes from dog livers were very efficient (70-100 % metabolism in 30 min) in metabolizing CSA. Hydroxylation and N-d emethylation accounted for most of the CSA metabolized in all the species t ested. 3. Microsomes from the small intestine produced qualitatively a similar met abolic profile as compared with the microsomes from the liver, but at a slo wer rate in all the species tested. The relative importance of the differen t metabolic pathways, however, differed between species. 4. This study points to the importance of recognizing the similarities and the differences in the metabolism of CSA in different species when data fro m animal studies are extrapolated to man.