Biochemical and analytical development of the CIME cocktail for drug fate assessment in humans

Rapid Communications in Mass Spectrometry : RCM
Orianne VideauHenri Bénech

Abstract

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 w...Continue Reading

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Citations

Dec 4, 2014·European Journal of Drug Metabolism and Pharmacokinetics·Natacha LenuzzaHenri Bénech
Mar 23, 2011·Expert Opinion on Drug Metabolism & Toxicology·Glynn A MorrishBruce Green
Oct 23, 2015·European Journal of Clinical Pharmacology·Thu Thuy NguyenNatacha Lenuzza
May 7, 2011·Journal of Pharmaceutical and Biomedical Analysis·Parul GorGregory A Reed
Dec 23, 2015·Pharmaceutical Statistics·Thu Thuy NguyenNatacha Lenuzza
Oct 31, 2012·Journal of Separation Science·Chih-Wei ChiuSung-Fang Chen
Feb 11, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Orianne VideauHenri Bénech
Jul 27, 2012·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·Régis BaudoinEric Leclerc
Nov 26, 2013·The American Journal of Pathology·Sabine Gerbal-ChaloinKarim Si-Tayeb

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