RESUMO
The present study illustrates the advantage of an isotope-IV study for the contribution analysis of metabolic tissues on systemic exposure of metabolites. A model parent drug, verapamil (VER), and its metabolite, norverapamil (Nor-VER), were used. This isotope-IV study used rats with and without the pre-treatment of the CYP inhibitor 1-aminobenzotriazole (ABT), was performed by the oral administration of VER (1 mg/kg) combined with the intravenous administration of stable isotope-labeled VER (VER-d6, 0.005 mg/kg). Plasma concentration profiles of both compounds and respective metabolites (Nor-VER, Nor-VER-d6) were then evaluated by LC-MSMS. VER oral availability was increased, and the systemic clearance decreased, in addition, the relative systemic exposure of Nor-VER and Nor-VER-d6 was increased by ABT pre-treatment. PK analyses revealed that, in ABT untreated rats, most Nor-VER in systemic circulation originated from the intestinal absorption process. ABT pre-treatment increased the contribution ratio to the systemic exposure of Nor-VER from the hepatic metabolism of systemically circulated VER, and decreased the contribution ratio of intestinal metabolism. These findings indicated that the isotope-IV study may be useful for considering the PK profile of metabolites.