Utility of mass spectrometry for in-vitro ADME assays.
A balance between pharmacological activity, safety and drug metabolism and pharmacokinetics (DMPK) attributes determines the fate of a new chemical entity (NCE) in drug discovery. Because of the increased number of NCEs requiring DMPK evaluation, several in vitro higher-throughput screens and counter screens designed to evaluate DMPK attributes have been introduced in drug discovery. The DMPK screens evaluate NCEs for potential absorption, metabolism, drug-drug interactions, brain penetration, protein binding and pharmacokinetics. Higher-throughput analytical methodologies for the determination of either a common end product of a screen or the parent compound (and/or possible metabolites) are essential for successful DMPK screens. Because of its speed, sensitivity and specificity, liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become the technology of choice for sample analysis. In this review, several in vitro screening assays that we employ in drug discovery are discussed with an emphasis on LC-MS/MS role in accelerating them.
Chu
Inhou
I
Exploratory Drug Metabolism, Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. inhou.chu@spcorp.com
Nomeir
Amin A
AA
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors / Q000378:metabolism; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D013058:Mass Spectrometry / Q000379:methods*; D008862:Microsomes, Liver / Q000201:enzymology; D004364:Pharmaceutical Preparations / Q000737:chemistry / Q000378:metabolism*; D010599:Pharmacokinetics; D026902:Potassium Channel Blockers / Q000378:metabolism; D011485:Protein Binding; D015203:Reproducibility of Results; D013678:Technology, Pharmaceutical / Q000379:methods
D018435:ATP Binding Cassette Transporter, Subfamily B; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D004791:Enzyme Inhibitors; D051638:Ether-A-Go-Go Potassium Channels; D004364:Pharmaceutical Preparations; D026902:Potassium Channel Blockers; D003577:Cytochrome P-450 Enzyme System