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

Canagliflozin (CNF) and dapagliflozin (DPF) are the first sodium-glucose cotransporter 2 inhibitors to be approved for clinical use. Although available evidence excludes clinically significant inhibition of cytochromes P450, the effects of CNF and DPF on human UDP-glucuronosyltransferase (UGT) enzymes are unknown. Here, we report the inhibition of human recombinant UGTs by CNF and DPF, along with the K_i values for selected recombinant and human liver microsomal UGTs. CNF inhibited all UGT1A subfamily enzymes, but the greatest inhibition was observed with UGT1A1, UGT1A9, and UGT1A10 (IC₅₀ values ≤ 10 µM). DPF similarly inhibited UGT1A1, UGT1A9, and UGT1A10, with IC₅₀ values ranging from 39 to 66 µM. In subsequent kinetic studies, CNF inhibited recombinant and human liver microsomal UGT1A9; K_i values ranged from 1.4 to 3.0 µM, depending on the substrate (propofol/4-methylumbelliferone) enzyme combination. K_i values for CNF inhibition of UGT1A1 were approximately 3-fold higher. Consistent with the activity screening data, DPF was a less potent inhibitor of UGT1A1 and UGT1A9. The K_i for DPF inhibition of UGT1A1 was 81 µM, whereas the K_i values for inhibition of UGT1A9 ranged from 12 to 15 µM. Based on the in vitro K_i values and plasma concentrations reported in the literature, DPF may be excluded as a perpetrator of DDIs arising from inhibition of UGT enzymes, but CNF inhibition of UGT1A1 and UGT1A9 in vivo cannot be discounted. Since the sodium-glucose cotransporter 2 inhibitors share common structural features, notably a glycoside moiety, investigation of drugs in this class for effects on UGT to identify (or exclude) potential drug-drug interactions is warranted.