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  • Title: The role of drug metabolism in cyclosporine A nephrotoxicity.
    Author: Burke MD, Whiting PH.
    Journal: Clin Nephrol; 1986; 25 Suppl 1():S111-6. PubMed ID: 3708920.
    Abstract:
    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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