Effect of etretinate on cyclosporin metabolism in vitro

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 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.

Update on retinoid therapy of psoriasis in: an update on the use of retinoids in dermatology

“…The combination of acitretin and cyclosporine carries the risk of cyclosporine accumulation because mediated cytochrome P‐450 system cyclosporine inactivation can be inhibited by acitretin (100). The combination of methotrexate and acitretin has been used in those patients in whom all other treatments have failed (101).…”

Cyclosporine Regimens in Plaque Psoriasis: An Overview with Special Emphasis on Dose, Duration, and Old and New Treatment Approaches

“…Lipid profiles must be closely monitored because both retinoids and CsA may increase serum cholesterol and triglyceride levels. No metabolic interaction has been demonstrated between CsA and etretinate in vitro [61]. Some reports in psoriatic patients however showed controversial results of combination of CsA and oral retinoids [62–64].…”

Therapeutic strategies: rotational therapy and combinations

“…42,43 This combination carries the risk of accumulation of cyclosporin as cyclosporin and acitretin are inactivated by the same cytochrome P-450 system. 44 The combination of cyclosporin and methotrexate has been indicated previously as contraindicated for safety reasons. 45 However, the combination has been used with success by rheumatologists.…”

“…However, the efficacy of the combination was not convincing 42,43 . This combination carries the risk of accumulation of cyclosporin as cyclosporin and acitretin are inactivated by the same cytochrome P‐450 system 44 . The combination of cyclosporin and methotrexate has been indicated previously as contraindicated for safety reasons 45 .…”