Coordinate induction of both cytochrome P4503A and MDRI by St John's wort in healthy subjects
Coordinate induction of both cytochrome P4503A and MDRI by St John's wort in healthy subjects
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DOI：
10.1067/mcp.2003.10
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发表时间：
2003-01-01
影响因子：
6.7
通讯作者：
Kim, RB
中科院分区：
文献类型：
--
作者：
Dresser, GK;Schwarz, UI;Kim, RB
工作背景：许多药物都是细胞色素P450（P450）3A和MDR 1的共底物;此外，它们的Back处置明显受到诱导剂（包括圣约翰草）预处理的影响。这种药物相互作用反映了通过涉及类固醇X受体/甾烷X受体的共同机制诱导两种蛋白质。然而，增强代谢和外排转运的相对贡献的整体inductionprocess.Methods：12天的预处理与圣约翰草的处置选择在体内探针药物的影响是未知的21名年轻健康受试者进行了测定。口服和静脉注射咪达唑仑后，用于评估CYP 3A活性在肠上皮和肝脏，而处置后的非索非那定。口服剂量被认为是一个衡量MDR 1功能，口服环孢素（INN，环孢素）的血药浓度-时间曲线被认为是反映CYP 3A和MDR 1 activity.Results：圣约翰草显着影响所有药物的血药浓度-时间曲线，与相关的清除率增加。对于咪达唑仑，静脉给药（约1.5倍）后的增强显著低于口服给药（约2.7倍），估计的肠和肝提取率约高1.2至1.4倍。相比之下，非索非那定和环孢素的口服清除率同样增加了约1.6倍和1.9倍，分别，这些变化都是统计学小于咪达唑仑的口服清除率和大于其估计的肠道extractions.Conclusions：虽然所有3种药物的处置。通过圣约翰草改变，通过口服清除率测量的诱导程度与CYP 3A活性（咪达唑仑）不同，明显比MDR 1功能（非索非那定）增加更多，而对于环孢素，口服清除率的变化似乎与MDR 1而不是CYP 3A的增加更密切相关，尽管这两种蛋白质都重要地参与了其处置。这些不一致性表明，虽然可能涉及一个共同的分子机制，定量方面的诱导是复杂的，并取决于特定的药物和相对贡献的CYP 3A和MDR 1在其处置。
Background: Many drugs are cosubstrates of cytochrome P450 (CYP) 3A and MDR1; furthermore, their Back disposition is markedly affected by pretreatment with inducing agents, including St John's wort. Such drug interactions reflect induction of both proteins through a common mechanism involving the steroid X receptor/pregnane X receptor. However, the relative contributions of enhanced metabolism and efflux transport to the overall induction process are unknown.Methods: The effects of 12 days' pretreatment with St John's wort on the disposition of selected in vivo probe drugs were determined in 21 young healthy subjects. Midazolam after oral and intravenous administration was used to assess CYP3A activity in both the intestinal epithelium and the liver, whereas the disposition of fexofenadine after an. oral dose was assumed to be a measure of MDR1 function, and the oral plasma concentration-time profile of cyclosporine (INN, ciclosporin) was considered to reflect both CYP3A and MDR1 activities.Results: St John's wort markedly affected the plasma concentration-time profiles of all of the drugs, with associated increases in their clearance. With midazolam, the enhancement was considerably less after intravenous administration (approximately 1.5-fold) than after oral administration (approximately 2.7-fold), and estimated intestinal and hepatic extraction ratios were higher by approximately 1.2- to 1.4-fold. By contrast, the, oral clearances of fexofenadine and cyclosporine were equally increased by approximately 1.6-fold and 1.9-fold, respectively; these changes were both statistically less than for midazolam's oral clearance and greater than its estimated intestinal extraction.Conclusions: Although the disposition of all 3 drugs was. altered by,St John's wort, the extent of induction measured by oral clearance was different with CYP3A activity (midazolam), apparently increasing more than MDR1 function (fexofenadine), whereas with cyclosporine the change in oral clearance appeared to be more closely associated with the increase in MDR1 rather than CYP3A, despite the fact that both proteins are importantly involved in its disposition. These discordances indicate that, although a common molecular mechanism may be involved, the quantitative aspects of-induction are complex and depend on the particular drug and the relative contributions of CYP3A and MDR1 in its disposition.