title: Inhibition of Human UDP-Glucuronosyltransferase Enzymes by Canagliflozin and Dapagliflozin: Implications for Drug-Drug Interactions.
abstract: 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 Ki 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; Ki values ranged from 1.4 to 3.0 µM, depending on the substrate (propofol/4-methylumbelliferone) enzyme combination. Ki 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 Ki for DPF inhibition of UGT1A1 was 81 µM, whereas the Ki values for inhibition of UGT1A9 ranged from 12 to 15 µM. Based on the in vitro Ki 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.
authors.affiliation: Department of Clinical Pharmacology (A.P., N.C., A.R., J.O.M.) and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia (A.R., J.O.M.).
authors.forename: Attarat
authors.initials: A
authors.lastname: Pattanawongsa
authors.affiliation: Department of Clinical Pharmacology (A.P., N.C., A.R., J.O.M.) and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia (A.R., J.O.M.).
authors.forename: Nuy
authors.initials: N
authors.lastname: Chau
authors.affiliation: Department of Clinical Pharmacology (A.P., N.C., A.R., J.O.M.) and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia (A.R., J.O.M.).
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowland
authors.affiliation: Department of Clinical Pharmacology (A.P., N.C., A.R., J.O.M.) and Flinders Centre for Innovation in Cancer, Flinders University School of Medicine, Adelaide, Australia (A.R., J.O.M.) john.miners@flinders.edu.au.
authors.forename: John O
authors.initials: JO
authors.lastname: Miners
mesh_terms: D001559:Benzhydryl Compounds / Q000378:metabolism* / Q000494:pharmacology; D000068896:Canagliflozin / Q000378:metabolism* / Q000494:pharmacology; D004347:Drug Interactions / Q000502:physiology; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D005960:Glucosides / Q000378:metabolism* / Q000494:pharmacology; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme
chemical_list: D001559:Benzhydryl Compounds; D000068896:Canagliflozin; D004791:Enzyme Inhibitors; D005960:Glucosides; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; D000099148:UGT1A1 Enzyme; C000715591:UGT1A9 protein, human; C529054:dapagliflozin