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使用创新型干血样采集方法对用于细胞色素P450表型分析的日内瓦鸡尾酒疗法中药物相互作用的评估。

Evaluation of Mutual Drug-Drug Interaction within Geneva Cocktail for Cytochrome P450 Phenotyping using Innovative Dried Blood Sampling Method.

作者信息

Bosilkovska Marija, Samer Caroline, Déglon Julien, Thomas Aurélien, Walder Bernhard, Desmeules Jules, Daali Youssef

机构信息

Division of Clinical Pharmacology and Toxicology, Geneva University Hospitals, Geneva, Switzerland.

Swiss Center for Applied Human Toxicology, Geneva, Switzerland.

出版信息

Basic Clin Pharmacol Toxicol. 2016 Sep;119(3):284-90. doi: 10.1111/bcpt.12586. Epub 2016 Apr 25.

Abstract

Cytochrome P450 (CYP) activity can be assessed using a 'cocktail' phenotyping approach. Recently, we have developed a cocktail (Geneva cocktail) which combines the use of low-dose probes with a low-invasiveness dried blood spots (DBS) sampling technique and a single analytical method for the phenotyping of six major CYP isoforms. We have previously demonstrated that modulation of CYP activity after pre-treatment with CYP inhibitors/inducer could be reliably predicted using Geneva cocktail. To further validate this cocktail, in this study, we have verified whether probe drugs contained in the latter cause mutual drug-drug interactions. In a randomized, four-way, Latin-square crossover study, 30 healthy volunteers received low-dose caffeine, flurbiprofen, omeprazole, dextromethorphan and midazolam (a previously validated combination with no mutual drug-drug interactions); fexofenadine alone; bupropion alone; or all seven drugs simultaneously (Geneva cocktail). Pharmacokinetic profiles of the probe drugs and their metabolites were determined in DBS samples using both conventional micropipette sampling and new microfluidic device allowing for self-sampling. The 90% confidence intervals for the geometric mean ratios of AUC metabolite/AUC probe for CYP probes administered alone or within Geneva cocktail fell within the 0.8-1.25 bioequivalence range indicating the absence of pharmacokinetic interaction. The same result was observed for the chosen phenotyping indices, that is metabolic ratios at 2 hr (CYP1A2, CYP3A) or 3 hr (CYP2B6, CYP2C9, CYP2C19, CYP2D6) post-cocktail administration. DBS sampling could successfully be performed using a new microfluidic device. In conclusion, Geneva cocktail combined with an innovative DBS sampling device can be used routinely as a test for simultaneous CYP phenotyping.

摘要

细胞色素P450(CYP)活性可采用“鸡尾酒”表型分析方法进行评估。最近,我们开发了一种鸡尾酒(日内瓦鸡尾酒),它将低剂量探针的使用与低侵入性干血斑(DBS)采样技术以及一种用于六种主要CYP同工型表型分析的单一分析方法相结合。我们之前已经证明,使用日内瓦鸡尾酒可以可靠地预测用CYP抑制剂/诱导剂预处理后CYP活性的调节情况。为了进一步验证这种鸡尾酒,在本研究中,我们验证了其中所含的探针药物是否会引起药物相互作用。在一项随机、四交叉、拉丁方交叉研究中,30名健康志愿者接受了低剂量咖啡因、氟比洛芬、奥美拉唑、右美沙芬和咪达唑仑(一种先前验证过的无药物相互作用的组合);单独的非索非那定;单独的安非他酮;或同时使用所有七种药物(日内瓦鸡尾酒)。使用传统微量移液器采样和允许自我采样的新型微流控装置,在DBS样本中测定探针药物及其代谢物的药代动力学特征。单独或在日内瓦鸡尾酒中给药的CYP探针的AUC代谢物/AUC探针几何平均比值的90%置信区间落在0.8 - 1.25生物等效性范围内,表明不存在药代动力学相互作用。对于所选的表型分析指标,即鸡尾酒给药后2小时(CYP1A2、CYP3A)或3小时(CYP2B6、CYP2C9、CYP2C19、CYP2D6)的代谢比值,也观察到了相同的结果。使用新型微流控装置可以成功地进行DBS采样。总之,日内瓦鸡尾酒与创新的DBS采样装置相结合可常规用作同时进行CYP表型分析的测试。

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