Effect of etretinate on cyclosporin metabolism in vitro

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Abstract
Cyclosporin (CyA) is an effective treatment for psoriasis, including cases unresponsive to other therapies. The major side-effect of CyA treatment is dose-related nephrotoxicity. Combinations of CyA and etretinate (Et) have been tested with a view to reducing CyA dose requirements, and therefore minimizing adverse effects. We have studied the effect of Et on the cytochrome P-450-mediated metabolism of CyA. Microsomes prepared from histoiogically normal human liver (obtained from four cadaver kidney transplant donors; all male: age range 21–56) were incubated with CyA and various concentrations of Et. Metabolism was quantified by high-performance liquid chromatography with radiometric detection, and metabolites tentatively identified from the retention times of authentic standards. After 30 min incubation of CyA and microsomal protein at 37°C, 10.1 ± 3.0% (mean±SD) 3H-CyA was converted to the monohydroxylated metabolites M1 and M17, and 3.3±0.8% to the N-demethylated metabolite M21. At an Et concentration of 100 μM inhibition of CyA hydroxylase and N-demethylase was in vitro: it is likely that the two drugs are metabolized by different P-450 isoenzymes.