Investigation into UDP-Glucuronosyltransferase (UGT) Enzyme Kinetics of Imidazole- and Triazole-Containing Antifungal Drugs in Human Liver Microsomes and Recombinant UGT Enzymes
Investigation into UDP-Glucuronosyltransferase (UGT) Enzyme Kinetics of Imidazole- and Triazole-Containing Antifungal Drugs in Human Liver Microsomes and Recombinant UGT Enzymes
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DOI：
10.1124/dmd.109.030676
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发表时间：
2010-06-01
影响因子：
3.9
通讯作者：
Jones, Barry
中科院分区：
文献类型：
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作者：
Bourcier, Karine;Hyland, Ruth;Jones, Barry
咪唑和三唑代表抗真菌唑衍生物的主要类别。关于UDP-葡萄糖醛酸基转移酶（UGT），药物代谢的焦点主要集中在其抑制作用，对唑类作为UGT的底物知之甚少。已有报道称，咪唑类抗真菌药物噻康唑和克罗康唑的N-葡萄糖醛酸代谢物，但目前尚无三唑类抗真菌药物N-葡萄糖醛酸化的报道。在本研究中，在人肝微粒体（HLM）中研究了含唑化合物的葡萄糖醛酸化证据。当鉴定出葡糖苷酸代谢产物时，在12种重组UGT（rUGT）酶中孵育唑类，并测定具有最强葡糖苷酸峰的UGT的酶动力学。本研究评价了6种咪唑类抗真菌药、3种三唑类和苯二氮卓类阿普唑仑（三唑）。所研究的化合物均被鉴定为UGT的底物。UGT 1A 4是参与所有化合物代谢的主要酶，但氟康唑主要由UGT 2B 7代谢，可能介导其O-葡糖苷酸代谢。还发现UGT 1A 3参与所有咪唑类药物的代谢，但不参与三唑类药物的代谢。在HLM和rUGT中，除伊曲康唑（8.4 μ M）外，咪唑类（14.8-144 μ M）的K（m）值均低于三唑类（158-3037 μ M）。所有研究的咪唑在高底物浓度下抑制其自身的代谢。在UGT 1A 4代谢方面，伊曲康唑显示了咪唑类而非三唑类抗真菌药的动力学特征。这种行为归因于伊曲康唑的物理化学性质与咪唑类药物在clogP方面相似。
Imidazoles and triazoles represent major classes of antifungal azole derivatives. With respect to UDP-glucuronosyltransferase (UGT) enzymes, the drug metabolism focus has mainly concentrated on their inhibitory effects with little known about azoles as substrates for UGTs. N-Glucuronide metabolites of the imidazole antifungals, tioconazole and croconazole, have been reported, but there are currently no reports of N-glucuronidation of triazole antifungal agents. In this study, evidence for glucuronidation of azole-containing compounds was studied in human liver microsomes (HLM). When a glucuronide metabolite was identified, azoles were incubated in 12 recombinant UGT (rUGT) enzymes, and enzyme kinetics were determined for the UGT with the most intense glucuronide peak. Six imidazole antifungals, three triazoles, and the benzodiazepine alprazolam (triazole) were evaluated in this study. All compounds investigated were identified as substrates of UGT. UGT1A4 was the main enzyme involved in the metabolism of all compounds except for fluconazole, which was mainly metabolized by UGT2B7, probably mediating its O-glucuronide metabolism. UGT1A3 was also found to be involved in the metabolism of all imidazoles but not triazoles. In both HLM and rUGT K(m) values were lower for imidazoles (14.8-144 mu M) than for triazoles (158-3037 mu M), with the exception of itraconazole (8.4 mu M). All of the imidazoles studied inhibited their own metabolism at high substrate concentrations. In terms of UGT1A4 metabolism, itraconazole showed kinetic features characteristic of imidazole rather than triazole antifungals. This behavior is attributed to the physicochemical properties of itraconazole that are similar to those of imidazoles in terms of clogP.