Amelioration of cyclosporin-induced nephrotoxicity in rats by induction of hepatic drug metabolism.

The aim of this study was to determine the effect of altered hepatic drug metabolism on the nephrotoxic and immunosuppressive properties of cyclosporin A (CsA) in the rat. From a consideration of the structures of those CsA metabolites identified so far, it seemed probable that the metabolism of CsA would occur at the hepatic cytochrome P-450 (cyt P-450) enzyme system. CsA (50 mg/kg/24 hr) administered orally for 14 days resulted in significant increases in both serum urea concentration and urinary N-acetyl-beta-D-glucosaminidase activity, accompanied by renal proximal tubular vacuolation. The concomitant administration of either Aroclor 1254 (25 mg/kg/24 hr, i.p.) or phenobarbitone (PB) (40 mg/kg/24 hr, i.p.) but not 3-methylcholanthrene (3-MC) (15 mg/kg/72 hr, i.p.) resulted in abolition of the nephrotoxicity, assessed both biochemically and histologically, whilst the suppressive effect on the humoral response to SRBC was unaltered. Phenobarbitone also significantly decreased serum CsA concentrations. These results suggest that the PB-inducible set of cyt P-450 isoenzymes may be responsible or partly responsible for hepatic CsA metabolism.