Biochemical and analytical development of the CIME cocktail for drug fate assessment in humans.
Biochemical and analytical development of the CIME cocktail for drug fate assessment in humans.
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用于人类药物命运评估的 CIME 鸡尾酒的生化和分析开发。
DOI：
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发表时间：
2010
影响因子：
2
通讯作者：
H. Bénech
中科院分区：
文献类型：
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作者：
Orianne Videau;M. Delaforge;M. Levi;E. Thévenot;Olivier Gal;L. Becquemont;P. Beaune;H. Bénech
基于药物代谢活性的表型分析似乎可以为药物开发过程中基于机制的相互作用提供信息。我们在这里报告创新CIME鸡尾酒开发的第一步。该混合物不仅适用于主要细胞色素P450，咖啡因、阿莫地喹、甲苯磺丁脲、奥美拉唑、美沙芬和咪达唑仑分别作为CYP 1A 2、CYP 2C 8、CYP 2C 9、CYP 2C 19、CYP 2D 6和CYP 3A的底物，还适用于II相酶UGT 1A 1/6/9与对乙酰氨基酚、P-gp和OATP 1B 1与地高辛和瑞舒伐他汀以及肾功能与美金刚。建立了一种采用1.7 μ m粒径色谱柱的超高效液相色谱法与串联质谱法（UPLC/MS/MS）相结合的测定方法，用于同时定量采用固相萃取法从人血浆中提取后的20种底物和代谢物。该方法在FDA指南的精神下进行了验证。平均准确度范围为87.7 - 115%，运行内和运行间的变异系数（CV%）分别为1.7 - 16.4%和1.6 - 14.9%，对于10批血浆的定量限（LOQ），准确度范围为84 - 115%，CV%精密度<16%。在恒温器（4 h，室温）、血浆（24 h，室温）、自动进样器（24 h，4 ℃）和血浆中的3个冻融循环中评价了短期稳定性。除3种分析物外，所有分析物在这些条件下均保持稳定。对于其他三个，可以遵循特定的过程。这种在人血浆中的稳健、快速和灵敏的测定为CIME混合物的十探针药物提供了分析工具。在不久的将来，将使用这种新的测定方法对临床样品进行测定。
Phenotyping based on drug metabolism activity appears to be informative regarding mechanism-based interactions during drug development. We report here the first steps of the development of the innovative CIME cocktail. This cocktail is designed not only for the major cytochrome P450, with caffeine, amodiaquine, tolbutamide, omeprazole, dextromethorphan and midazolam as substrates of CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6 and CYP3A, respectively, but also phase II enzymes UGT 1A1/6/9 with acetaminophen, P-gp and OATP1B1 with digoxin and rosuvastatin, and renal function with memantine. An assay combining ultra-performance liquid chromatography using a 1.7 microm particle size column with tandem mass spectrometry (UPLC/MS/MS) was set up for the simultaneous quantification of the 20 substrates and metabolites after extraction from human plasma using solid-phase extraction. The method was validated in the spirit of the FDA guidelines. Mean accuracy ranged from 87.7 to 115%, the coefficient of variance (CV%) of intra- and inter-run from 1.7 to 16.4% and from 1.6 to 14.9%, respectively, and for the limit of quantification (LOQ) with ten lots of plasma, accuracy ranged from 84 to 115% and CV% precision was <16%. Short-term stability was evaluated in eluate (4 h, room temperature), plasma (24 h, room temperature), the autosampler (24 h, 4 degrees C) and in three freeze/thaw cycles in plasma. All except three analytes were stable under these conditions. For the three others a specific process can be followed. This robust, fast and sensitive assay in human plasma provides an analytical tool for ten-probe drugs of the CIME cocktail. Clinical samples will be assayed in the near future using this new assay method.
DOI：
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发表时间：
2001-07
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
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作者：
M. Bruce;S. Hall;B. Haehner‐Daniels;J. Gorski
通讯作者：
M. Bruce;S. Hall;B. Haehner‐Daniels;J. Gorski
影响因子：
5.8
作者：
J. Gorski;J. Gorski;S. Hall;David R. Jones;M. Vandenbranden
通讯作者：
J. Gorski;J. Gorski;S. Hall;David R. Jones;M. Vandenbranden