Production of human metabolites of cyclosporin A, AM1, AM4N and AM9, by microbial conversion

In humans, cyclosporin A (CyA) is primarily metabolized to two hydroxylated (AM1 and AM9) and one N -demethylated (AM4N) derivative. To produce these derivatives, 1237 actinomycetes were screened for their ability to convert CyA. Among them, 89 strains (7.2%) produced these derivatives from CyA. Finally, Dactylosporangium variesporum IFO 14104, Actinoplanes sp. ATCC 53771 and Streptosporangium sp. AF935 were selected for the production of AM1, AM4N, and AM9, respectively. Composition of the production medium and the incubation period with CyA were important for obtaining a high yield of CyA derivatives. Large-scale microbial conversion of CyA (1.5 g) using a 30- l jar fermentor yielded 288 mg of AM1 (19.2%), 147 mg of AM4N (9.8%) and 115 mg of AM9 (7.7%).