Abstract

Canagliflozin (CNF) and dapaliflozin (DPF) are the first SGLT2 inhibitors to be approved for clinical use. Although available evidence excludes clinically significant inhibition of cytochromes P450, 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 K_i values for selected recombinant and human liver microsomal UGTs. CNF inhibited all UGT1A subfamily enzymes, but greatest inhibition was observed with UGT 1A1, 1A9 and 1A10 (IC₅₀ values ≤ 10 μM). DPF similarly inhibited UGT 1A1, 1A9 and 1A10, with IC₅₀ values ranging from 39 - 66 μM. In subsequent kinetic studies, CNF inhibited recombinant and human liver microsomal UGT1A9; K_i values ranged from 1.4 - 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, while 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 SGLT2 inhibitors share common structural features, notably a glycoside moiety, investigation of drugs in this class for effects on UGT to identify (or exclude) potential DDIs is warranted.