NON-LINEAR PHARMACOKINETICS OF MISONIDAZOLE AND DESMETHYLMISONIDAZOLE IN THE ISOLATED PERFUSED-RAT-LIVER

Abstract

Dose-dependent elimination of misonidazole (MISO) and its metabolite demethylmisonidazole (DEMISO) [radiosensitizers used in cancer therapy] were investigated in the isolated perfused rat liver and saturation kinetics were observed for both compounds. The simplest model which accurately described the DEMISO clearance from the perfusate consisted of a saturable elimination pathway (Vmax3 [maximal conversion rate] = 32 nmol/min, Km2 = 11 .mu.M) in parallel with a 1st-order pathway [CL5 (clearance) = 0.21 ml/min]. A similar model was constructed for MISO (Vmax2 = 110 nmol/min, Km2 = 10 .mu.M, CL4 = 0.36 ml/min), but required an additional saturable pathway (Vmax1 = 226 nmol/min, Km = 1850 .mu.M) to characterize the generation of DEMISO, as suggested by in vitro microsomal studies. A good correlation was demonstrated between DEMISO perfusate concentrations (generated during the course of MISO perfusions) and simulations based on the MISO model which included the microsomal data. The MISO and DEMISO models demonstrate that the relative contributions of the different pathways for MISO and DEMISO elimination are strongly concentration-dependent and that the MISO .fwdarw. DEMISO pathway is a minor route. A qualitative similarity in saturation kinetics was observed in the disappearance curves for both MISO and DEMISO from the liver perfsuate. MISO in combination with an excess of DEMISO resulted in a marked decrease in the clearance rate of MISO from the liver perfusate. Evidently MISO and DEMISO are metabolized along similar pathways.