Increasing Speed and Throughput When Using HPLC-MS/MS Systems forDrug Metabolism and Pharmacokinetic Screening

Yunsheng      Hsieh; Walter      A. Korfmacher

doi:10.2174/138920006777697963

Abstract

Both combinatorial chemistry and parallel synthesis provide a valuable means for the production of large num-bers of compounds with diverse molecular architectures that become available for various drug discovery experiments. Inboth the lead optimization and lead selection stages, one requirement that is common for many processes is the need forbioanalytical support. This review summarizes current high throughput strategies and efficient methodologies that are em-ployed for drug metabolism and pharmacokinetic (DMPK) screens for a series of drug discovery compounds. For thesetypes of assays, high performance liquid chromatography coupled to a tandem mass spectrometer (HPLC-MS/MS) hasnow become the technique of choice. The major high throughput strategies including sample reduction and cassette dosingare discussed. The methods for increasing the speed of HPLC-MS/MS-based analyses, such as fast chromatography, di-rect sample injection, parallel technologies and combined ionization interfaces are also pr esented in this review. In addi-tion, the special challenges when performing HPLC-MS/MS bioanalysis, such as the choice of ionization sources, matrixionization suppression and the potential for endogenous interferences, are addressed.

Keywords: HPLC, DMPK, HPLC-MS/MS, Throughput, Cassette dosing, PK Screening, ADME

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