Nonlinear pharmacokinetics of misonidazole and desmethylmisonidazole in the isolated perfused rat liver

Abstract

Dose-dependent elimination of misonidazole (MISO) and its metabolite desmethylmisonidazole (DESMISO) were investigated in the isolated perfused rat liver and saturation kinetics were observed for both compounds. The simplest model which accurately described the DESMISO clearance from the perfusate consisted of a saturable elimination pathway (Vmax 3 = 32 nmol/min, Km3 = 11 micro M) in parallel with a first-order pathway [CL5 (clearance) = 0.21 ml/min]. A similar model was constructed for MISO (Vmax2 = 110 nmol/min, Km2 = 10 micro M, CL4 = 0.36 ml/min), but required an additional saturable pathway (Vmax1 = 226 nmol/min, Km1 = 1850 micro M) to characterize the generation of DESMISO, as suggested by in vitro microsomal studies. A good correlation was demonstrated between DESMISO perfusate concentrations (generated during the course of MISO perfusion) and simulations based on the MISO model which included the microsomal data. The MISO and DESMISO models demonstrate that the relative contributions of the different pathways for MISO and DESMISO elimination are strongly concentration-dependent and that the MISO leads to DESMISO pathway is a minor route. A qualitative similarity in saturation kinetics was observed in the disappearance curves for both MISO and DESMISO from the liver perfusate. MISO In combination with an excess of DESMISO resulted in a marked decrease in the clearance rate of MISO from the liver perfusate. This observation suggest that MISO and DESMISO are metabolized along similar pathways.