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.

Difference in the Pharmacokinetics and Hepatic Metabolism of Antidiabetic Drugs in Zucker Diabetic Fatty and Sprague-Dawley Rats

“…A species difference was observed for canagliflozin regarding the abundance of metabolite formation. Metabolite A, the alcohol oxidation product, was the predominant metabolite in rat and also has been reported as a rodent-specific product (Mamidi et al, 2014), whereas the glucuronidation metabolite B was the most abundant in human ( Fig. 3A; Table 2).…”

“…Species difference in metabolite formation from canagliflozin was reported in the in vivo metabolite identification experiments. UGTmediated O-glucuronidation was the major clearance pathway in human, whereas in rats, oxidation and oxidation-plus-glucuronidation products were the predominant pathways, with the alcohol oxidation of metabolite A being most abundant (Mamidi et al, 2014). In humans, UGT1A9 and UGT2B4 are responsible for the formation of the two O-glucuronidation metabolites, respectively (Francke et al, 2015), and CYP3A4 contributes to the formation of a minor hydroxylation metabolite (Mamidi et al, 2014), which was not detected as one of the major metabolites in human or rat hepatocytes in the present study.…”

“…UGTmediated O-glucuronidation was the major clearance pathway in human, whereas in rats, oxidation and oxidation-plus-glucuronidation products were the predominant pathways, with the alcohol oxidation of metabolite A being most abundant (Mamidi et al, 2014). In humans, UGT1A9 and UGT2B4 are responsible for the formation of the two O-glucuronidation metabolites, respectively (Francke et al, 2015), and CYP3A4 contributes to the formation of a minor hydroxylation metabolite (Mamidi et al, 2014), which was not detected as one of the major metabolites in human or rat hepatocytes in the present study. In the substrate depletion assay, no difference in UGT-mediated glucuronidation between the two strains was observed despite significantly lower UGT activity in ZDF compared with SD rats when the UGT probe substrate 4-MU was used.…”

Clinical Pharmacokinetic, Pharmacodynamic, and Drug–Drug Interaction Profile of Canagliflozin, a Sodium-Glucose Co-transporter 2 Inhibitor

“…2) [23]. The unchanged drug accounted for the major drug-related component in the plasma (canagliflozin: *57 %; metabolites: *43 %) in healthy participants [20].…”

Inhibition of Human UDP-Glucuronosyltransferase Enzymes by Canagliflozin and Dapagliflozin: Implications for Drug-Drug Interactions

“…1), and available evidence indicates that glucuronidation of the glucoside moiety is the major metabolic pathway of both compounds in humans. CNF is glucuronidated at the 2-and 3-hydroxyl groups of the glucoside rings; the respective glucuronides are referred to as M5 and M7 (Mamidi et al, 2014). The urinary excretion of M5 and M7 in patients with type 2 diabetes ranges from 7 to 10% and 21 to 32% of the administered dose, respectively (Devineni et al, 2013).…”