The role of drug metabolism in cyclosporine A nephrotoxicity.
In rats cyclosporine A (CsA) caused decreases in the hepatic microsomal P-450-dependent mono-oxygenase enzyme system and in glucuronyl transferase. The decrease in the mono-oxygenase was transient and may have been due to self-limiting suicide inactivation of P-450 by a CsA metabolite. Changes in hepatic mono-oxygenase activity over a period of 7 weeks were associated with a converse oscillation in CsA nephrotoxicity, indicating that CsA was detoxified by hepatic P-450. This impression was strengthened by observations that induction of P-450 by low-dose phenobarbitone led to decreases in both the circulating levels and nephrotoxicity of CsA, whereas cotreatment with the P-450 inhibitor ketoconazole caused increases in CsA circulating levels and nephrotoxicity. Induction by 3-methylcholanthrene had no effect. Cobaltous chloride, which suppresses the synthesis of P-450, exacerbated CsA nephrotoxicity. Neither cimetidine nor SKF-525A, both P-450 inhibitors, had any effect.
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D000633:Aminopyrine N-Demethylase / Q000378:metabolism; D000818:Animals; D003524:Cyclosporins / Q000378:metabolism / Q000633:toxicity*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004790:Enzyme Induction / Q000187:drug effects; D007674:Kidney Diseases / Q000139:chemically induced* / Q000378:metabolism; D008748:Methylcholanthrene / Q000494:pharmacology; D008862:Microsomes, Liver / Q000201:enzymology; D006899:Mixed Function Oxygenases / Q000378:metabolism; D010634:Phenobarbital / Q000494:pharmacology; D051381:Rats
D003524:Cyclosporins; D008748:Methylcholanthrene; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; D000633:Aminopyrine N-Demethylase; D010634:Phenobarbital