title: Inhibition potential of glimepiride (gli) towards important UDP-glucuronosyltransferase (UGT) isoforms in human liver.
abstract: The aim of the present study was to investigate the inhibitory potential of glimepiride towards important UDP-glucuronosyltransferase (UGT) isoforms in human liver, which play a key role in the elimination of drugs. The recombinant UGT enzymes were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. The results showed that 100 microM of glimepiride inhibited UGT1A1, UGT1A3, UGT1A6, UGT1A9, UGT2B7 and UGT2B15 by 54.7%, 43.1%, 100%, 70.5%, 32.7 and 37.2%, respectively. Given that glimepiride exhibited strong inhibition towards UGT1A6, further inhibitory kinetic behaviour was determined. Glimepiride exerted concentration-dependent inhibition towards UGT1A6. Both Dixon and Lineweaver-Burk plots demonstrated that inhibition of UGT1A6 was best fit for noncompetitive inhibition type, and the inhibition kinetic parameter (Ki) was calculated to be 59.8 microM. Given that UGT1A6 plays a key role in detoxification of many drugs, more attention should be given when glimepiride was co-administered with the drugs mainly undergoing UGT1A6-mediated metabolism.
authors.affiliation: Endocrinology Department, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China.
authors.forename: Jian-Fang
authors.initials: JF
authors.lastname: Fu
authors.forename: Qin-You
authors.initials: QY
authors.lastname: Ren
authors.forename: Nan-Yan
authors.initials: NY
authors.lastname: Zhang
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Yan-Yang
authors.initials: YY
authors.lastname: Tu
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Fu
authors.forename: Dao-Hai
authors.initials: DH
authors.lastname: Li
authors.forename: Yong-Sheng
authors.initials: YS
authors.lastname: Zhang
mesh_terms: D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D013379:Substrate Specificity; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007527:Isoenzymes; D013453:Sulfonylurea Compounds; D006923:Hymecromone; C057619:glimepiride; D014453:Glucuronosyltransferase