Contribution analysis of metabolic tissues on systemic exposure of an active metabolite after oral administration of verapamil using a stable isotope-labeled compound.

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. Copyright © 2023 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Citation

Makoto Kataoka, Shota Ohshiro, Keiko Minami, Tsubasa Hasegawa, Haruki Higashino, Toshihide Takagi, Kazutaka Togashi, Kuninori Mutaguchi, Shinji Yamashita. Contribution analysis of metabolic tissues on systemic exposure of an active metabolite after oral administration of verapamil using a stable isotope-labeled compound. Drug metabolism and pharmacokinetics. 2023 Aug;51:100514

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PMID: 37364522

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