Effects of the immunosuppressant FK-506 and its analog FK-520 on hepatic and renal cytochrome P450 mixed-function oxidase.
The novel immunosuppressant FK-506 and its analog FK-520 were found to inhibit the hepatic microsomal mixed-function oxidase system in male Sprague-Dawley rats. At 5 and 10 mg/kg/day, s.c., for 6 days they caused 30-80% decreases in cytochrome P450 levels, NADPH-cytochrome P450 reductase, and benzphetamine N-demethylase activities. The metabolism of FK-506 itself was inhibited by 50%. FK-506 and FK-520 had a minimal effect on the renal cytochrome P450 levels unlike cyclosporin A which produced a 67% increase after six daily 25 mg/kg doses. A single dose of FK-506 (25 mg/kg, s.c.) had a minimal effect on the hepatic or renal metabolizing enzyme system. In vitro, addition of FK-506 and FK-520 to human and control rat liver microsomes resulted in a concentration-dependent inhibition of benzphetamine N-demethylation (10-20% at 50 microM, 60-75% at 250 microM). We suggest that in view of its potential to inhibit hepatic cytochrome P450-dependent mixed-function oxidase, resulting in the inhibition of its own metabolism, FK-506 should be administered with caution to transplant patients.
Vincent
S H
SH
Department of Animal and Exploratory Drug Metabolism, Merck Sharp & Dohme Research Laboratories, Rahway, NJ 07065.
Wang
R W
RW
Karanam
B V
BV
Klimko
M
M
Alvaro
R
R
Chiu
S H
SH
D015660:7-Alkoxycoumarin O-Dealkylase / Q000037:antagonists & inhibitors; D000328:Adult; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors*; D010089:Oxidoreductases, N-Demethylating / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D016559:Tacrolimus / Q000031:analogs & derivatives
D000900:Anti-Bacterial Agents; D003524:Cyclosporins; D065607:Cytochrome P-450 Enzyme Inhibitors; D007166:Immunosuppressive Agents; D010880:Piperidines; D003577:Cytochrome P-450 Enzyme System; C058028:immunomycin; D006899:Mixed Function Oxygenases; D015660:7-Alkoxycoumarin O-Dealkylase; C019781:benzphetamine N-demethylase; D010089:Oxidoreductases, N-Demethylating; D016559:Tacrolimus