METABOLISM OF CYCLOSPORINE-G IN THE MOUSE, RAT, AND DOG

Cyclosporin G (CsG; Sandoz compound OG 37-325) is a cyclic undecapepti de with potent, immunosuppressive activity and is currently in clinica l testing for prevention of transplanted solid organ rejection. Althou gh structurally similar to cyclosporin A (CsA), results in animals sug gest that CsG has a reduced potential for nephrotoxicity when compared with CsA, while retaining equivalent therapeutic efficacy. In the pre sent study, the major metabolic pathways of CsG in the mouse, rat, and dog were investigated using radiolabeled drug substance to determine if interspecies differences in metabolism exist. The results indicated that the major metabolic pathways in these animal species are similar to those previously reported for CsA, including oxidative modificatio ns at amino acids 1, 4, and 9, and concomitant cyclization of amino ac id 1 in two of these metabolites. Moreover, the seven major CsG metabo lites (designated GM19, GM1c9, GM4N9, GM1, GM9, GM1c, and GM4N) observ ed in animal excreta and/or blood were identical to those identified i n humans. The major circulating metabolite in blood was GM9 (9-hydroxy lated CsG) in all species. In addition, numerous unidentified minor me tabolites were observed. Renal excretion was a minor elimination pathw ay, with the majority of drug-related material excreted via the fecal route. In conclusion, CsG was found to proceed through the same metabo lic pathways in three animal species and humans, and that species diff erences in metabolism were primarily because of differences in the rel ative importance of the pathways observed.