title: Metabolite profiling and enzyme reaction phenotyping of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, in humans.
abstract: 1. To understand the clearance mechanism of luseogliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, we investigated its human metabolite profile and metabolic enzymes responsible for the primary metabolic pathways in human using reaction phenotyping. 2. Sixteen metabolites of luseogliflozin were found in human plasma and/or urine and their structural information indicated that the drug was metabolized via multiple metabolic pathways. The primary metabolic pathways involve (1) O-deethylation to form M2 and subsequent glucuronidation to form M12, (2) ω-hydroxylation at ethoxy group to form M3 followed by oxidation to form the corresponding carboxylic acid metabolite (M17) and (3) direct glucuronidation to form M8. 3. The reaction phenotyping studies indicated that the formation of M2 was mainly mediated by cytochrome P450 (CYP) 3A4/5, and subsequently M12 formation was catalyzed by UGT1A1, UGT1A8 and UGT1A9. The formation of M3 was mediated by CYP4A11, CYP4F2 and CYP4F3B, and the further oxidation of M3 to M17 was mediated by alcohol dehydrogenase and aldehyde dehydrogenase. The formation of M8 was catalyzed by UGT1A1. 4. These results demonstrate that luseogliflozin is metabolized through multiple pathways, including CYP-mediated oxidation and glucuronidation, in human.
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Atsunori
authors.initials: A
authors.lastname: Miyata
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hachiuma
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Haruyuki
authors.initials: H
authors.lastname: Mori
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Horiuchi
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Mizuno-Yasuhira
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Chino
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Shigeji
authors.initials: S
authors.lastname: Jingu
authors.affiliation: b Clinical Development, Taisho Pharmaceutical Co., Ltd , Tokyo , Japan.
authors.forename: Soichi
authors.initials: S
authors.lastname: Sakai
authors.affiliation: c Research and Development Headquarters, Taisho Pharmaceutical Co., Ltd , Tokyo , Japan , and.
authors.forename: Yoshishige
authors.initials: Y
authors.lastname: Samukawa
authors.affiliation: d Development Headquarters, Taisho Pharmaceutical Co., Ltd , Tokyo , Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nakai
authors.affiliation: a Department of Pharmacokinetics and Metabolism , Drug Safety and Pharmacokinetics Laboratories, Taisho Pharmaceutical Co., Ltd , Saitama , Japan.
authors.forename: Jun-Ichi
authors.initials: JI
authors.lastname: Yamaguchi
mesh_terms: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005947:Glucose; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D006900:Hydroxylation; D007700:Kinetics; D053858:Metabolic Networks and Pathways; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol / Q000031:analogs & derivatives* / Q000378:metabolism; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
chemical_list: D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System; D005947:Glucose; D014453:Glucuronosyltransferase; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013012:Sorbitol; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C549343:1,5-anhydro-1-(5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl)-1-thioglucitol; C510163:CYP3A4 protein, human; C454320:UDP-glucuronosyltransferase, UGT1A8
keywords: CYP; SGLT2 inhibitor; UGT; luseogliflozin; metabolism