In vitro metabolism of TAK-438, vonoprazan fumarate, a novel potassium-competitive acid blocker. (2nd December 2017)

• Record Type: Journal Article
• Authors: Yamasaki, Hitomi; Kawaguchi, Naohiro; Nonaka, Masami; Takahashi, Junzo; Morohashi, Akio; Hirabayashi, Hideki; Moriwaki, Toshiya; Asahi, Satoru
• Is Part Of: Xenobiotica. Volume 47:Number 12(2017)
• Page Start: 1027
• Page End: 1034
• Publication Date: 2017-12-02
• Subjects: CYP2C19 -- CYP3A4 -- oxidation -- P-CAB -- sulfation -- SULT2A1; Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• DOI: 10.1080/00498254.2016.1203505
• Languages: English
• ISSNs: 0049-8254

Abstract

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 of 14 C-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.