title: Tacrolimus strongly inhibits multiple human UDP-glucuronosyltransferase (UGT) isoforms.
abstract: The objective of the present study is to clearly evaluate the inhibitory effects of tacrolimus (tacro) on important UGT isoforms in human liver, including determination of inhibition kinetic type and calculation of inhibition kinetic parameters. An in vitro incubation system was used to investigate the inhibitory effect of tacro on UGT isoforms. The recombinant UGT isoforms were used as enzyme source, and a nonspecific substrate 4-methylumbelliferone (4-MU) was utilized as substrate. Among the tested UGT isoforms, UGT1A1, UGT1A3, UGT2B7 and UGT2B15 were strongly inhibited by tacro in a concentration-dependent manner. Dixon and Lineweaver-Burk plots showed that the inhibition of UGT1A1, UGT1A3, and UGT2B7 was all best fit to competitive inhibition type, and the inhibition of UGT2B15 was best fit to noncompetitive type. The inhibition kinetic parameters (Ki) were determined to be 4.7, 1.3, 1.9, and 4.3 microM for UGT1A1, UGT1A3, UGT2B7, and UGT2B15, respectively. Inhibition of these important UGT isoforms in human liver might be an important reason for clinically frequent drug-drug interaction between tacro and other drugs.
authors.affiliation: Department of Organ Transplantation, Zhujiang Hospital, Nanfang Medical University, Dalian, China.
authors.forename: Xiao-You
authors.initials: XY
authors.lastname: Liu
authors.forename: Zhong-Ze
authors.initials: ZZ
authors.lastname: Fang
authors.forename: Pei-Pei
authors.initials: PP
authors.lastname: Dong
authors.forename: Xiang-Hua
authors.initials: XH
authors.lastname: Shi
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Teng
authors.forename: Xu-Yong
authors.initials: XY
authors.lastname: Sun
mesh_terms: D001711:Biotransformation; D004791:Enzyme Inhibitors; D020719:Glucuronides / Q000378:metabolism; D014453:Glucuronosyltransferase / Q000037:antagonists & inhibitors*; D006801:Humans; D006923:Hymecromone / Q000031:analogs & derivatives / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D020719:Glucuronides; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; D007527:Isoenzymes; D011994:Recombinant Proteins; D006923:Hymecromone; D014453:Glucuronosyltransferase; D016559:Tacrolimus