Effect of etretinate on cyclosporin metabolism in vitro

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 histologically normal human (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 degrees 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 microM inhibition of CyA hydroxylase and N-demethylase was < 20%. This study indicates that there is no metabolic interaction between CyA and Et in vitro; it is likely that the two drugs are metabolized by different P-450 isoenzymes.