Abstract

Canagliflozin is an oral antihyperglycemic agent used for the treatment of type 2 diabetes mellitus that blocks the reabsorption of glucose in the proximal renal tubule by inhibiting the sodium glucose co transporter 2. This article describes the in vivo biotransformation and disposition of canagliflozin after a single oral dose of [¹⁴C]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 animals and humans. In BDC mice and rats, the majority of radioactivity was excreted in bile. The extent of radioactivity excreted in urine as a percentage of the administered [¹⁴C]canagliflozin dose was 1.2 to 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, 2 pharmacologically inactive O glucuronide conjugates of canagliflozin, M5 and M7, represented 19 and 14% of total drug related exposure and were considered as 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 liver had significant exposure to M5 and M7. Pharmacological inactivity and high water solubility of M5 and M7 support glucuronidation of canagliflozin as a safe detoxification pathway.