Fu Jian-Fang, Ren Qin-You, Zhang Nan-Yan, Gao Bin, Tu Yan-Yang, Fu Guo-Qiang, Li Dao-Hai, Zhang Yong-Sheng
Endocrinology Department, Xijing Hospital, Fourth Military Medical University, Xi'an, Shanxi, China.
Pharmazie. 2012 Aug;67(8):715-7.
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.
本研究的目的是调查格列美脲对人肝脏中重要的尿苷二磷酸葡萄糖醛酸转移酶（UGT）同工型的抑制潜力，这些同工型在药物消除中起关键作用。使用重组UGT酶作为酶源，并利用非特异性底物4-甲基伞形酮（4-MU）作为底物。结果表明，100微摩尔的格列美脲分别抑制UGT1A1、UGT1A3、UGT1A6、UGT1A9、UGT2B7和UGT2B15达54.7%、43.1%、100%、70.5%、32.7%和37.2%。鉴于格列美脲对UGT1A6表现出强烈抑制作用，进一步测定了其抑制动力学行为。格列美脲对UGT1A6表现出浓度依赖性抑制。Dixon图和Lineweaver-Burk图均表明，对UGT1A6的抑制最符合非竞争性抑制类型，抑制动力学参数（Ki）经计算为59.8微摩尔。鉴于UGT1A6在许多药物的解毒过程中起关键作用，当格列美脲与主要经UGT1A6介导代谢的药物合用时，应给予更多关注。
