title: Increasing speed and throughput when using HPLC-MS/MS systems for drug metabolism and pharmacokinetic screening.
abstract: Both combinatorial chemistry and parallel synthesis provide a valuable means for the production of large numbers of compounds with diverse molecular architectures that become available for various drug discovery experiments. In both the lead optimization and lead selection stages, one requirement that is common for many processes is the need for bioanalytical support. This review summarizes current high throughput strategies and efficient methodologies that are employed for drug metabolism and pharmacokinetic (DMPK) screens for a series of drug discovery compounds. For these types of assays, high performance liquid chromatography coupled to a tandem mass spectrometer (HPLC-MS/MS) has now become the technique of choice. The major high throughput strategies including sample reduction and cassette dosing are discussed. The methods for increasing the speed of HPLC-MS/MS-based analyses, such as fast chromatography, direct sample injection, parallel technologies and combined ionization interfaces are also presented in this review. In addition, the special challenges when performing HPLC-MS/MS bioanalysis, such as the choice of ionization sources, matrix ionization suppression and the potential for endogenous interferences, are addressed.
authors.affiliation: Exploratory Drug Metabolism, Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA. yunsheng.hsieh@spcorp.com
authors.forename: Yunsheng
authors.initials: Y
authors.lastname: Hsieh
authors.forename: Walter A
authors.initials: WA
authors.lastname: Korfmacher
mesh_terms: D000818:Animals; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D008832:Microchemistry / Q000379:methods; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D015203:Reproducibility of Results; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods
chemical_list: D004364:Pharmaceutical Preparations