Liquid chromatography/tandem mass spectrometric quantification with metabolite screening as a strategy to enhance the early drug discovery process.
Throughput for early discovery drug metabolism studies can be increased with the concomitant acquisition of metabolite screening information and quantitative analysis using ultra-fast gradient chromatographic methods. Typical ultra-fast high-performance liquid chromatography (HPLC) parameters used during early discovery pharmacokinetic (PK) studies, for example, employ full-linear gradients over 1-2 min at very high flow rates (1.5-2 mL/min) on very short HPLC columns (2 x 20 mm). These conditions increase sample throughput by reducing analytical run time without sacrificing chromatographic integrity and may be used to analyze samples generated from a variety of in vitro and in vivo studies. This approach allows acquisition of more information about a lead candidate while maintaining rapid analytical turn-around time. Some examples of this approach are discussed in further detail.
Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA. philip_tiller@merck.com
Philip R
PR
Tiller
Leslie A
LA
Romanyshyn
D000818:Animals; D001702:Biopharmaceutics / Q000295:instrumentation / Q000379:methods*; D001711:Biotransformation; D002317:Cardiovascular Agents / Q000032:analysis / Q000493:pharmacokinetics; D002478:Cells, Cultured; D002626:Chemistry, Pharmaceutical / Q000295:instrumentation / Q000379:methods*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000295:instrumentation / Q000379:methods*; D020719:Glucuronides / Q000032:analysis; D000882:Haplorhini; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000032:analysis / Q000493:pharmacokinetics; D051379:Mice; D008862:Microsomes, Liver / Q000378:metabolism*; D010599:Pharmacokinetics; D051381:Rats; D013045:Species Specificity; D021241:Spectrometry, Mass, Electrospray Ionization / Q000379:methods*
D002317:Cardiovascular Agents; D020719:Glucuronides; D007004:Hypoglycemic Agents