Influence of pretreatment with immunosuppressants on O-demethylation of dextromethorphan in isolated perfused rat liver.

Changes in the immune system induced by exogenous or endogenous factors may be accompanied with modifications of the activity of the drug metabolising enzymes in the liver. Some immunostimulatory agents are known to suppress the oxidative metabolism mediated by cytochromes P450. Possible effects of substances which suppress the immune responses of the organism have not been fully understood yet. The present study was undertaken to investigate the influence of immunosuppressants cyclophosphamide and dexamethasone on the CYP2D 1-dependent metabolism of dextromethorphan (DEM) in the isolated perfused liver from male rat donors (Wistar albino, 250-310 g). Recirculatory perfusion system was used with Williams' medium E (Sigma Chemicals Co.) as a perfusion medium (120 mL). DEM was administered as a 1 mg bolus into the perfusion solution at the start of each experiment after 20 min preperfusion. Samples of perfusate for HPLC determination of DEM and its O-demethylated metabolite dextrorphan (DOR) were taken at 15 min intervals for 120 min. The results have shown a rapid conversion of DEM to DOR in the isolated rat liver preparations. Pharmacokinetic parameters in the livers from intact rats were as follows: t1/2 DEM = 19.1+/-4.10 min, k(m) = 0.035+/-0.008 min(-1), Cl(m) = 4.21+/-0.97 mL x min(-1), AUC(DOR) = 2160+/-201 microg x min x L(-1). Pretreatment of rats with dexamethasone (4 mg/kg/day, iv, x 3 days) led to a significant increase in the concentration of dextrorphan in the recirculating solution, but it did not substantially change the kinetic constants of DOR formation (km = 0.036+/-0.004 min(-1), Cl(m) = 4.27+/-0.43 mL x min(-1)). Cyclophosphamide (100 mg/kg, ip, 1 dose on day 5 before perfusion) induced nearly twofold increase in the DOR concentrations in perfusate and thus highly significant (p < 0.01) changes of the kinetic parameters characterizing the increased rate of conversion of DEM to DOR (t1/2 DEM = 12.1+/-0.90 min, km = 0.055+/-0.004 min(-1), Cl(m) = 7.09+/-1.37 mL x min(-1), AUC(DOR) = 3602+/-154 microg x min x L(-1)). Considering that both cyclophosphamide and dexamethasone belong to the most widely used immunosuppressive drugs, their potential to promote the CYP2D-mediated metabolism might have a clinical impact in combined therapy of autoimmune or other diseases.