Evaluation of cytochrome P450 inhibition assays using human liver microsomes by a cassette analysis /LC-MS/MS

Drug Metabolism Letters
Serenella ZambonMahmud Kajbaf

Abstract

In vitro inhibition assays are used to screen new chemical entities (NCEs) for inhibition studies by using human liver microsomes. High-throughput inhibition assays using pooling methods have been developed to keep pace with screening requirements at the lead ADME stage. This method can determine IC(50) NCEs using microsomes from various organs from any species. A cassette analysis inhibition assay for five of the major CYP enzymes (phenacetin for CYP1A2, diclofenac for CYP2C9, (S)-mephenytoin for CYP2C19, bufurarol for CYP2D6 and midazolam, nifedipine and atorvastatin for CYP3A4) in pooled human liver microsomes using ultraperformance liquid chromatography tandem mass spectrometry (LC/MS/MS) were developed. The major metabolites of seven CYP-specific probe substrates for the five P450 isoforms were monitored and quantified to determine IC(50) values. Human liver microsomal incubation samples at each test compound concentration were combined and analyzed simultaneously by the LC/MS/MS method. The incubation was performed using the selective CYP inhibitors for each isoform: fluvoxamine (CYP1A2), sulphaphenazole (CYP2C9), ticlopidine (CYP2C19), quinidine (CYP2D6), and Ketoconazole (CYP3A4). Similar IC(50) results were obtained us...Continue Reading

Citations

Apr 23, 2013·European Archives of Psychiatry and Clinical Neuroscience·Taro KishiNakao Iwata
Dec 6, 2011·Archives of Pharmacal Research·Dong Hee NaHye Suk Lee
Mar 24, 2015·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·V VijayabhaskarSriram Rajagopal
May 25, 2012·Drug and Chemical Toxicology·María Luisa LuceroAna Alejandro
Nov 29, 2013·Journal of Labelled Compounds & Radiopharmaceuticals·Marzena Poraj-KobielskaMartin Hofrichter
Aug 15, 2012·Bioorganic & Medicinal Chemistry·J AtzrodtJ Zimmermann
Apr 9, 2020·International Journal of Molecular Sciences·Alyssa C McVeyMartin Welch
Mar 20, 2018·Archives of Pharmacal Research·Jung Jae JoSangkyu Lee

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