title: In vitro profiling of the metabolism and drug-drug interaction of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, using human liver microsomes, human hepatocytes, and recombinant human CYP.
abstract: Abstract 1. The metabolism and drug-drug interaction (DDI) risk of tofogliflozin, a potent and highly specific sodium-glucose co-transporter 2 inhibitor, were evaluated by in vitro studies using human liver microsomes, human hepatocytes, and recombinant human CYPs. 2. The main metabolite of tofogliflozin was the carboxylated derivative (M1) in human hepatocytes, which was the same as in vivo. The metabolic pathway of tofogliflozin to M1 was considered to be as follows: first, tofogliflozin was catalyzed to the primary hydroxylated derivative (M4) by CYP2C18, CYP4A11 and CYP4F3B, then M4 was oxidized to M1. 3. Tofogliflozin had no induction potential on CYP1A2 and CYP3A4. Neither tofogliflozin nor M1 had inhibition potential on CYPs, with the exception of a weak CYP2C19 inhibition by M1. 4. Not only are multiple metabolic enzymes involved in the tofogliflozin metabolism, but the drug is also excreted into urine after oral administration, indicating that tofogliflozin is eliminated through multiple pathways. Thus, the exposure of tofogliflozin would not be significantly altered by DDI caused by any co-administered drugs. Also, tofogliflozin seems not to cause significant DDI of co-administered drugs because tofogliflozin has no CYP induction or inhibition potency, and the main metabolite M1 has no clinically relevant CYP inhibition potency.
authors.affiliation: Research Division, Chugai Pharmaceutical Co., Ltd. , Shizuoka , Japan .
authors.forename: Mizuki
authors.initials: M
authors.lastname: Yamane
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kawashima
authors.forename: Koji
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Nagao
authors.forename: Mika
authors.initials: M
authors.lastname: Sato
authors.forename: Masayuki
authors.initials: M
authors.lastname: Suzuki
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Honda
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hagita
authors.forename: Olaf
authors.initials: O
authors.lastname: Kuhlmann
authors.forename: Agnes
authors.initials: A
authors.lastname: Poirier
authors.forename: Stephen
authors.initials: S
authors.lastname: Fowler
authors.forename: Christoph
authors.initials: C
authors.lastname: Funk
authors.forename: Sandrine
authors.initials: S
authors.lastname: Simon
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Aso
authors.forename: Sachiya
authors.initials: S
authors.lastname: Ikeda
authors.forename: Masaki
authors.initials: M
authors.lastname: Ishigai
mesh_terms: D001559:Benzhydryl Compounds / Q000737:chemistry / Q000378:metabolism*; D002250:Carbon Radioisotopes; D003067:Coenzymes / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D004347:Drug Interactions; D004790:Enzyme Induction / Q000187:drug effects; D005960:Glucosides / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055442:Metabolome / Q000187:drug effects; D055432:Metabolomics / Q000379:methods*; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000378:metabolism; D051297:Sodium-Glucose Transporter 2 / Q000378:metabolism; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D013997:Time Factors
chemical_list: D001559:Benzhydryl Compounds; D002250:Carbon Radioisotopes; D003067:Coenzymes; D065607:Cytochrome P-450 Enzyme Inhibitors; D005960:Glucosides; D011994:Recombinant Proteins; D051297:Sodium-Glucose Transporter 2; D000077203:Sodium-Glucose Transporter 2 Inhibitors; D003577:Cytochrome P-450 Enzyme System; C575086:6-((4-ethylphenyl)methyl)-3',4',5',6'-tetrahydro-6'-(hydroxymethyl)spiro(isobenzofuran-1(3H),2'-(2H)pyran)-3',4',5'-triol
keywords: CYP; SGLT2; diabetes mellitus; induction; inhibition; metabolism