Human liver cytochrome P4503A biotransformation of the cyclosporin derivative SDZ IMM 125.

In humans, cytochrome P4503A (CYP3A) is the major cytochrome P450 gene family that metabolizes SDZ IMM 125 (IMM) to its primary metabolites. Human liver microsomes could be used for this study, because the metabolite profile matched that found in human blood. The apparent affinity (KM) of IMM for the cytochrome P450 proteins (5.1 +/- 1.8 microM) is similar to that of cyclosporin A (CSA). CSA competitively inhibited the metabolism of IMM, increasing the KM 2- and 4.6-fold in the presence of 4 and 10 microM CSA, respectively (Ki 3.8 +/- 1.1 microM). Ketoconazole exhibited competitive inhibition kinetics toward IMM biotransformation, increasing the KM of IMM 1.8-fold at 0.5 microM ketoconazole and 3.5-fold at 1 microM ketoconazole, with no effect on Vmax (Ki of 0.5 +/- 0.4 microM). These results indicate that both CSA and ketoconazole would cause drug interactions, interfering with the biotransformation of IMM. The metabolism of IMM was also greatly inhibited (approximately 80%) by the CYP3A suicide substrate triacetyloleandomycin and a CYP3A inhibitory antibody, indicating the involvement of CYP3A proteins in the biotransformation of IMM. Confirmation of CYP3A4 involvement in the formation of the three primary IMM metabolites was demonstrated with recombinant cells expressing human CYP3A4. Therefore, compounds interacting with CYP3A proteins are expected to cause drug-drug interactions (i.e. the antimycotics ketoconazole and clotrimazole, the steroids ethinylestradiol and testosterone, the ergots, the calcium channel blocker nifedipine, and the immunosuppressants FK-506 and rapamycin).(ABSTRACT TRUNCATED AT 250 WORDS)