title: In vitro metabolism of TAK-438, vonoprazan fumarate, a novel potassium-competitive acid blocker.
abstract: 1. TAK-438, vonoprazan fumarate, is a novel orally active potassium-competitive acid blocker, developed as an antisecretory drug. In this study, we investigated the in vitro metabolism of14C-labeled TAK-438. In human hepatocytes, M-I, M-II, M-III and M-IV-Sul were mainly formed, and these were also detected in clinical studies. N-demethylated TAK-438 was also formed as an in vitro specific metabolite. Furthermore, CYP3A4 mainly contributed to the metabolism of TAK-438 to M-I, M-III, and N-demethylated TAK-438, and CYP2B6, CYP2C19 and CYP2D6 partly catalyzed the metabolism of TAK-438. The sulfate conjugation by SULT2A1 also contributed to the metabolism of TAK-438 to form TAK-438 N-sulfate, and CYP2C9 mediated the formation of M-IV-Sul from TAK-438 N-sulfate. The metabolite M-IV, which could be another possible intermediate in the formation of M-IV-Sul, was not observed as a primary metabolite of TAK-438 in any of the in vitro studies. 2. In conclusion, TAK-438 was primarily metabolized by multiple metabolizing enzymes including CYP3A4, CYP2B6, CYP2C19, CYP2D6, and a non-CYP enzyme SULT2A1, and the influence of the CYP2C19 genotype status on gastric acid suppression post TAK-438 dosing could be small. The multiple metabolic pathways could also minimize the effects of co-administrated CYP inhibitors or inducers on the pharmacokinetics of TAK-438.
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Hitomi
authors.initials: H
authors.lastname: Yamasaki
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kawaguchi
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Nonaka
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Junzo
authors.initials: J
authors.lastname: Takahashi
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Morohashi
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Hirabayashi
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Toshiya
authors.initials: T
authors.lastname: Moriwaki
authors.affiliation: a Drug Metabolism and Pharmacokinetics Research Laboratories, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , Kanagawa , Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Asahi
mesh_terms: D065731:Cytochrome P-450 CYP2C19 / Q000378:metabolism; D005765:Gastrointestinal Agents / Q000493:pharmacokinetics*; D011758:Pyrroles / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: C552956:1-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl)-N-methylmethanamine; D005765:Gastrointestinal Agents; D011758:Pyrroles; D013449:Sulfonamides; D065731:Cytochrome P-450 CYP2C19
keywords: CYP2C19; CYP3A4; P-CAB; SULT2A1; oxidation; sulfation