PMID- 25834030
OWN - NLM
STAT- MEDLINE
DCOM- 20160128
LR  - 20211203
IS  - 1521-009X (Electronic)
IS  - 0090-9556 (Linking)
VI  - 43
IP  - 6
DP  - 2015 Jun
TI  - Targeted screen for human UDP-glucuronosyltransferases inhibitors and the 
      evaluation of potential drug-drug interactions with zafirlukast.
PG  - 812-8
LID - 10.1124/dmd.114.062141 [doi]
AB  - 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.
CI  - Copyright (c) 2015 by The American Society for Pharmacology and Experimental 
      Therapeutics.
FAU - Oda, Shingo
AU  - Oda S
AD  - 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.).
FAU - Fujiwara, Ryoichi
AU  - Fujiwara R
AD  - 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.).
FAU - Kutsuno, Yuki
AU  - Kutsuno Y
AD  - 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.).
FAU - Fukami, Tatsuki
AU  - Fukami T
AD  - 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.).
FAU - Itoh, Tomoo
AU  - Itoh T
AD  - 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.).
FAU - Yokoi, Tsuyoshi
AU  - Yokoi T
AD  - 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.).
FAU - Nakajima, Miki
AU  - Nakajima M
AD  - 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.
LA  - eng
PT  - Journal Article
DEP - 20150401
PL  - United States
TA  - Drug Metab Dispos
JT  - Drug metabolism and disposition: the biological fate of chemicals
JID - 9421550
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Indoles)
RN  - 0 (Isoenzymes)
RN  - 0 (Leukotriene Antagonists)
RN  - 0 (Phenylcarbamates)
RN  - 0 (Recombinant Proteins)
RN  - 0 (Selective Estrogen Receptor Modulators)
RN  - 0 (Small Molecule Libraries)
RN  - 0 (Sulfonamides)
RN  - 0 (Tosyl Compounds)
RN  - 4F86W47BR6 (Raloxifene Hydrochloride)
RN  - EC 2.4.1.- (bilirubin uridine-diphosphoglucuronosyl transferase 1A10)
RN  - EC 2.4.1.17 (Glucuronosyltransferase)
RN  - EC 2.4.1.17 (UDP-glucuronosyltransferase, UGT1A8)
RN  - XZ629S5L50 (zafirlukast)
SB  - IM
MH  - Drug Evaluation, Preclinical
MH  - Drug Interactions
MH  - Enzyme Inhibitors/adverse effects/*pharmacology
MH  - Glucuronosyltransferase/*antagonists & inhibitors/genetics/metabolism
MH  - Humans
MH  - Indoles
MH  - Intestinal Mucosa/drug effects/enzymology
MH  - Intestine, Small/*drug effects/enzymology
MH  - Isoenzymes/antagonists & inhibitors/genetics/metabolism
MH  - Kinetics
MH  - Leukotriene Antagonists/adverse effects/metabolism/*pharmacology
MH  - *Metabolic Detoxication, Phase II
MH  - Microsomes/*drug effects/enzymology
MH  - Microsomes, Liver/drug effects/enzymology
MH  - Phenylcarbamates
MH  - Raloxifene Hydrochloride/metabolism
MH  - Recombinant Proteins/chemistry/metabolism
MH  - Selective Estrogen Receptor Modulators/metabolism
MH  - Small Molecule Libraries
MH  - Substrate Specificity
MH  - Sulfonamides
MH  - Tosyl Compounds/adverse effects/metabolism/*pharmacology
EDAT- 2015/04/03 06:00
MHDA- 2016/01/29 06:00
CRDT- 2015/04/03 06:00
PHST- 2014/11/18 00:00 [received]
PHST- 2015/04/01 00:00 [accepted]
PHST- 2015/04/03 06:00 [entrez]
PHST- 2015/04/03 06:00 [pubmed]
PHST- 2016/01/29 06:00 [medline]
AID - dmd.114.062141 [pii]
AID - 10.1124/dmd.114.062141 [doi]
PST - ppublish
SO  - Drug Metab Dispos. 2015 Jun;43(6):812-8. doi: 10.1124/dmd.114.062141. Epub 2015 
      Apr 1.