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

Canagliflozin, used to treat type 2 diabetes mellitus (T2DM), is commonly co-administered with sulfonylureas. The objective of the present study was to evaluate the possible inhibitory effect of sulfonylureas and non-steroidal anti-inflammatory drugs (NSAIDs) on canagliflozin metabolism in vitro. Three sulfonylurea derivatives were evaluated as inhibitors: chlorpropamide, glimepiride and gliclazide. Two other NSAIDs were used as positive control inhibitors: niflumic acid and diclofenac. The rate of formation of canagliflozin metabolites was determined by HPLC analysis of in vitro incubations of canagliflozin as a substrate with and without inhibitors, using human liver microsomes (HLMs). Among sulfonylureas, glimepiride showed the most potent inhibitory effect against canagliflozin M7 metabolite formation, with an IC value of 88 μm, compared to chlorpropamide and gliclazide with IC values of more than 500 μm. Diclofenac inhibited M5 metabolite formation more than M7, with IC values of 32 μm for M5 and 80 μm for M7. Niflumic acid showed no inhibition activity against M5 formation, but had relatively selective inhibitory potency against M7 formation, which is catalysed by UGT1A9, with an IC value of 1.9 μm and an inhibition constant value of 0.8 μm. A clinical pharmacokinetic interaction between canagliflozin and sulfonylureas is unlikely. However, a possible clinically important drug interaction between niflumic acid and canagliflozin has been identified.