In vitro metabolism of canagliflozin in human liver, kidney, intestine microsomes, and recombinant uridine diphosphate glucuronosyltransferases (UGT) and the effect of genetic variability of UGT enzymes on the pharmacokinetics of canagliflozin in humans

Abstract

O-glucuronidation is the major metabolic elimination pathway for canagliflozin. The objective was to identify enzymes and tissues involved in the formation of 2 major glucuronidated metabolites (M7 and M5) of canagliflozin and subsequently to assess the impact of genetic variations in these uridine diphosphate glucuronosyltransferases (UGTs) on in vivo pharmacokinetics in humans. In vitro incubations with recombinant UGTs revealed involvement of UGT1A9 and UGT2B4 in the formation of M7 and M5, respectively. Although M7 and M5 were formed in liver microsomes, only M7 was formed in kidney microsomes. Participants from 7 phase 1 studies were pooled for pharmacogenomic analyses. A total of 134 participants (mean age, 41 years; men, 63%; white, 84%) were included in the analysis. In UGT1A9*3 carriers, exposure of plasma canagliflozin (Cmax,ss , 11%; AUCτ,ss , 45%) increased relative to the wild type. An increase in exposure of plasma canagliflozin (Cmax,ss , 21%; AUCt,ss , 18%) was observed in participants with UGT2B4*2 genotype compared with UGT2B4*2 noncarriers. Metabolites further delineate the role of both enzymes. The pharmacokinetic findings in participants carrying the UGT1A9*3 and UGT2B4*2 allele implicate that UGT1A9 and UGT2B4 are involved in the metabolism of canagliflozin to M7 and M5, respectively.

Inhibitory effects of sulfonylureas and non‐steroidal anti‐inflammatory drugs on in vitro metabolism of canagliflozin in human liver microsomes

“…Following in vitro incubation of canagliflozin, chromatographic peaks presumed to correspond to the two principal glucuronide metabolites M5 and M7 were detected in addition to the peak corresponding to remaining canagliflozin (Figure ). The presumed glucuronide metabolite peaks are consistent with those definitively identified in previous studies (Francke et al, ; Mamidi et al, ). They were not detected in the absence of UDPGA, and increased with increasing canagliflozin concentration and incubation time with UDPGA added (Figure ).…”

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

“…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.…”

Sodium–Glucose Cotransporter 2 Inhibitors: A Case Study in Translational Research

“…Two uridine 5′-diphospho-glucuronosyltransferases (UGTs), UGT2B4 and UGT1A9, catalyze the formation of M5 and M7, respectively. Genetic variants in UGT1A9 and UGT2B4 have modest effects on canagliflozin pharmacokinetics ( 37 ).…”