Suppr超能文献

唑类抗真菌药对丁丙诺啡、美沙酮和羟考酮体外代谢的抑制作用。

Azole antifungal inhibition of buprenorphine, methadone and oxycodone in vitro metabolism.

作者信息

Moody David E, Liu Fenyun, Fang Wenfang B

机构信息

Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, 30 E 2000 S, Rm 105, Salt Lake City, UT 84112, USA

Center for Human Toxicology, Department of Pharmacology and Toxicology, University of Utah, 30 E 2000 S, Rm 105, Salt Lake City, UT 84112, USA.

出版信息

J Anal Toxicol. 2015 Jun;39(5):374-86. doi: 10.1093/jat/bkv030. Epub 2015 Apr 12.

Abstract

Opioid-related mortality rates have escalated. Drug interactions may increase blood concentrations of the opioid. We therefore used human liver microsomes (HLMs) and cDNA-expressed human cytochrome P450s (rCYPs) to study in vitro inhibition of buprenorphine metabolism to norbuprenorphine (CYP3A4 and 2C8), oxycodone metabolism to noroxycodone (CYP3A4 and 2C18) and oxymorphone (CYP2D6), and methadone metabolism to R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP; CYP3A4 and 2B6). In this study, we have examined the inhibitory effect of 12 (mostly antifungal) azoles. These compounds have a wide range of solubility; to keep organic solvent ≤1%, there was an equally wide range of highest concentration tested (e.g., itraconazole 5 µM to fluconazole 1000 µM). Inhibitors were first incubated with HLMs at three concentrations with or without preincubation of inhibitor with reducing equivalents to also screen for time-dependent inhibition (TDI). Posaconazole displayed evidence of TDI; metronidazole and albendazole had no significant effect. Azoles were next screened at the highest achievable concentration for non-CYP3A4 pathways. IC50 values (µM) were determined for most CYP3A4 pathways (ranges) and other pathways as dictated by screen results: clotrimazole (0.30 - 0.35; others >30 µM); econazole (2.2 - 4.9; 2B6 R-EDDP - 9.5, S-EDDP - 6.8; 2C8 - 6.0; 2C18 - 1.0; 2D6 - 1.2); fluconazole (7.7 - 66; 2B6 - 313, 361; 2C8 - 1240; 2C18 - 17; 2D6 - 1000); itraconazole (2.5 to >5; others >5); ketoconazole (0.032 - 0.094; 2B6 - 12, 31; 2C8 - 78; 2C18 - 0.98; 2D6 - 182); miconazole (2.3 - 7.6; 2B6 - 2.8, 2.8; 2C8 - 5.3; 2C18 - 3.1; 2D6 - 5.9); posaconazole (3.4 - 20; 2C18 - 3.8; others >30); terconazole (0.48 to >10; 2C18 - 8.1; others >10) and voriconazole (0.40 - 15; 2B6 - 2.4, 2.5; 2C8 - 170; 2C18 - 13; 2D6 >300). Modeling based on estimated Ki values and plasma concentrations from the literature suggest that the orally administered azoles, particularly ketoconazole and voriconazole, have the greatest potential for inhibiting CYP3A4 pathways, as does voriconazole for the CYP2B6 pathways. Azoles used for mucosal and topical applications did not exceed the modeling threshold.

摘要

阿片类药物相关的死亡率不断上升。药物相互作用可能会提高阿片类药物的血药浓度。因此,我们使用人肝微粒体(HLMs)和cDNA表达的人细胞色素P450(rCYPs)来研究体外对丁丙诺啡代谢为去甲丁丙诺啡(CYP3A4和2C8)、羟考酮代谢为去甲羟考酮(CYP3A4和2C18)以及羟吗啡酮(CYP2D6),和美沙酮代谢为R -和S - 2 -亚乙基-1,5 -二甲基-3,3 -二苯基吡咯烷(EDDP;CYP3A4和2B6)的抑制作用。在本研究中,我们检测了12种(大多为抗真菌)唑类药物的抑制作用。这些化合物的溶解度范围很广;为使有机溶剂≤1%,所测试的最高浓度范围也同样很广(例如,伊曲康唑5 μM至氟康唑1000 μM)。抑制剂首先与HLMs在三种浓度下孵育,有或没有将抑制剂与还原当量预孵育,以筛查时间依赖性抑制(TDI)。泊沙康唑显示出TDI的证据;甲硝唑和阿苯达唑没有显著影响。接下来在可达到的最高浓度下对非CYP3A4途径的唑类药物进行筛查。针对大多数CYP3A4途径(范围)和根据筛查结果确定的其他途径测定IC50值(μM):克霉唑(0.30 - 0.35;其他>30 μM);益康唑(2.2 - 4.9;2B6 R - EDDP - 9.5,S - EDDP - 6.8;2C8 - 6.0;2C18 - 1.0;2D6 - 1.2);氟康唑(7.7 - 66;2B6 - 313,361;2C8 - 1240;2C18 - 17;2D6 - 1000);伊曲康唑(2.5至>5;其他>5);酮康唑(0.032 - 0.094;2B6 - 12,31;2C8 - 78;2C18 - 0.98;2D6 - 182);咪康唑(2.3 - 7.6;2B6 - 2.8,2.8;2C8 - 5.3;2C18 - 3.1;2D6 - 5.9);泊沙康唑(3.4 - 20;2C18 - 3.8;其他>30);特康唑(0.48至>10;2C18 - 8.1;其他>10)和伏立康唑(0.40 - 15;2B6 - 2.4,2.5;2C8 - 170;2C18 - 13;2D6>300)。基于文献中估计的Ki值和血浆浓度进行的建模表明,口服唑类药物,尤其是酮康唑和伏立康唑,对CYP3A4途径的抑制潜力最大,伏立康唑对CYP2B6途径也是如此。用于黏膜和局部应用的唑类药物未超过建模阈值。

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验