title: Metabolism and excretion of canagliflozin in mice, rats, dogs, and humans.
abstract: Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus. It blocks the reabsorption of glucose in the proximal renal tubule by inhibiting the sodium-glucose cotransporter 2. This article describes the in vivo biotransformation and disposition of canagliflozin after a single oral dose of [(14)C]canagliflozin to intact and bile duct-cannulated (BDC) mice and rats and to intact dogs and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in both animals and humans. In BDC mice and rats, most radioactivity was excreted in bile. The extent of radioactivity excreted in urine as a percentage of the administered [(14)C]canagliflozin dose was 1.2%-7.6% in animals and approximately 33% in humans. The primary pathways contributing to the metabolic clearance of canagliflozin were oxidation in animals and direct glucuronidation of canagliflozin in humans. Unchanged canagliflozin was the major component in systemic circulation in all species. In human plasma, two pharmacologically inactive O-glucuronide conjugates of canagliflozin, M5 and M7, represented 19% and 14% of total drug-related exposure and were considered major human metabolites. Plasma concentrations of M5 and M7 in mice and rats from repeated dose safety studies were lower than those in humans given canagliflozin at the maximum recommended dose of 300 mg. However, biliary metabolite profiling in rodents indicated that mouse and rat livers had significant exposure to M5 and M7. Pharmacologic inactivity and high water solubility of M5 and M7 support glucuronidation of canagliflozin as a safe detoxification pathway.
authors.affiliation: Janssen Research & Development, Raritan, New Jersey (R.N.V.S.M., S.S., D.D., M.D.J.), Janssen Research & Development, Spring House, Pennsylvania (J.C., D.K., R.L., J.S., D.C.E., M.F.K., H.K.L.), and Janssen Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium (F.C., E.S.).
authors.forename: Rao N V S
authors.initials: RN
authors.lastname: Mamidi
authors.forename: Filip
authors.initials: F
authors.lastname: Cuyckens
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Ellen
authors.initials: E
authors.lastname: Scheers
authors.forename: Dennis
authors.initials: D
authors.lastname: Kalamaridis
authors.forename: Ronghui
authors.initials: R
authors.lastname: Lin
authors.forename: Jose
authors.initials: J
authors.lastname: Silva
authors.forename: Sue
authors.initials: S
authors.lastname: Sha
authors.forename: David C
authors.initials: DC
authors.lastname: Evans
authors.forename: Michael F
authors.initials: MF
authors.lastname: Kelley
authors.forename: Damayanthi
authors.initials: D
authors.lastname: Devineni
authors.forename: Mark D
authors.initials: MD
authors.lastname: Johnson
authors.forename: Heng Keang
authors.initials: HK
authors.lastname: Lim
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000818:Animals; D001646:Bile / Q000378:metabolism; D000068896:Canagliflozin; D002250:Carbon Radioisotopes; D004285:Dogs; D005243:Feces / Q000737:chemistry; D005260:Female; D005960:Glucosides / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D020719:Glucuronides / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013876:Thiophenes / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D002250:Carbon Radioisotopes; D005960:Glucosides; D020719:Glucuronides; D007004:Hypoglycemic Agents; D013876:Thiophenes; D000068896:Canagliflozin