Microbial biotransformation products of cyclosporin A.
In order to mimic the human metabolic pathway of cyclosporin A (CyA) a total of 28 bacterial and 72 fungal strains was screened for their ability to transform CyA. Among 3 bacteria and 11 fungi, which produced the main human metabolite OL-17 [eta HyMeBmt1]CyA, Actinoplanes sp. (ATCC 53771) achieved the best transformation rate (5.4%). Furthermore, the two N-demethylated minor products [Leu4]CyA (3.2%) and [Leu9]CyA (4.7%) were isolated, both known as minor natural metabolites and the first one also as a human biotransformation product. Microbial conversion of CyA using the actinomycete Sebekia benihana (NRRL 11111) yielded [gamma HyMeLeu4]CyA (35%), [gamma HyLeu4]CyA (4.5%) and [gamma HyMeLeu4, gamma HyMeLeu6]CyA (8.6%). The structures of these derivatives correspond with those of the human metabolic pathway. The related compounds [Nva2]CyA (CyG) and [D-MeSer3]CyA were similarly converted to the corresponding 4-gamma-hydroxylated analogues. None of the biotransformation products showed a better immunosuppressive effect than CyA, although in various cases the cyclophilin binding affinity was comparable to that of CyA.
Kuhnt
M
M
Preclinical Research, Sandoz Pharma Ltd, Basle, Switzerland.
Bitsch
F
F
France
J
J
Hofmann
H
H
Sanglier
J J
JJ
Traber
R
R
D001419:Bacteria / Q000378:metabolism*; D001711:Biotransformation; D016572:Cyclosporine / Q000493:pharmacokinetics*; D005658:Fungi / Q000378:metabolism*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics*
D007166:Immunosuppressive Agents; D016572:Cyclosporine