title: Targeted screen for human UDP-glucuronosyltransferases inhibitors and the evaluation of potential drug-drug interactions with zafirlukast.
abstract: Inhibition of drug metabolizing enzymes is a major mechanism in drug-drug interactions (DDIs). A number of cases of DDIs via inhibition of UDP-glucuronosyltranseferases (UGTs) have been reported, although the changes in pharmacokinetics are relatively small in comparison with drugs that are metabolized by cytochrome P450s. Most of the past studies have investigated hepatic UGTs, although recent studies have revealed a significant contribution of UGTs in the small intestine to drug clearance. To evaluate potential DDIs caused by inhibition of intestinal UGTs, we assessed inhibitory effects of 578 compounds, including drugs, xenobiotics, and endobiotics, on human UGT1A8 and UGT1A10, which are major contributors to intestinal glucuronidation. We identified 29 inhibitors by monitoring raloxifene glucuronidation with recombinant UGTs. All of the inhibitors potently inhibited UGT1A1 activity, as well. We found that zafirlukast is a potent general inhibitor of UGT1As and a moderate inhibitor of UGT2Bs because it monitors 4-methylumbelliferone glucuronidation by recombinant UGTs. However, zafirlukast did not potently inhibit diclofenac glucuronidation, suggesting that the inhibitory effects might be substrate specific. Inhibitory effects of zafirlukast on some UGT substrates were further investigated in human liver and human small intestine microsomes in order to evaluate potential DDIs. The R values (the ratios of intrinsic clearance with and without an inhibitor) revealed that zafirlukast has potential to cause clinical DDIs in the small intestine. Although we could not identify specific UGT1A8 and UGT1A10 inhibitors, zafirlukast was identified as a general inhibitor for UGTs in vitro. The present study suggests that the inhibition of UGT in the small intestine would be an underlying mechanism for DDIs.
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (S.O., T.F., T.Y., M.N.); and School of Pharmacy, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan (R.F., Y.K, T.I.).
authors.forename: Shingo
authors.initials: S
authors.lastname: Oda
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (S.O., T.F., T.Y., M.N.); and School of Pharmacy, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan (R.F., Y.K, T.I.).
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Fujiwara
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (S.O., T.F., T.Y., M.N.); and School of Pharmacy, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan (R.F., Y.K, T.I.).
authors.forename: Yuki
authors.initials: Y
authors.lastname: Kutsuno
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (S.O., T.F., T.Y., M.N.); and School of Pharmacy, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan (R.F., Y.K, T.I.).
authors.forename: Tatsuki
authors.initials: T
authors.lastname: Fukami
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (S.O., T.F., T.Y., M.N.); and School of Pharmacy, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan (R.F., Y.K, T.I.).
authors.forename: Tomoo
authors.initials: T
authors.lastname: Itoh
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (S.O., T.F., T.Y., M.N.); and School of Pharmacy, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan (R.F., Y.K, T.I.).
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Yokoi
authors.affiliation: Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan (S.O., T.F., T.Y., M.N.); and School of Pharmacy, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan (R.F., Y.K, T.I.) nmiki@p.kanazawa-u.ac.jp.
authors.forename: Miki
authors.initials: M
authors.lastname: Nakajima
mesh_terms: D004353:Drug Evaluation, Preclinical; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007211:Indoles; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D007421:Intestine, Small / Q000187:drug effects* / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D007700:Kinetics; D020024:Leukotriene Antagonists / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*; D050217:Metabolic Detoxication, Phase II; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D048448:Phenylcarbamates; D020849:Raloxifene Hydrochloride / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D020845:Selective Estrogen Receptor Modulators / Q000378:metabolism; D054852:Small Molecule Libraries; D013379:Substrate Specificity; D013449:Sulfonamides; D014105:Tosyl Compounds / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D007527:Isoenzymes; D020024:Leukotriene Antagonists; D048448:Phenylcarbamates; D011994:Recombinant Proteins; D020845:Selective Estrogen Receptor Modulators; D054852:Small Molecule Libraries; D013449:Sulfonamides; D014105:Tosyl Compounds; D020849:Raloxifene Hydrochloride; C476725:bilirubin uridine-diphosphoglucuronosyl transferase 1A10; D014453:Glucuronosyltransferase; C454320:UDP-glucuronosyltransferase, UGT1A8; C062735:zafirlukast