Pharmacokinetic screening for the selection of new drug discovery candidates is greatly enhanced through the use of liquid chromatography-atmospheric pressure ionization tandem mass spectrometry.
Selection of a new drug discovery candidate from a series of compounds requires a means of performing rapid analytical method development and sensitive quantitation of each drug in serum, plasma or other biological matrices. Information on serum/plasma concentration, bioavailability and half-life can often aid the discovery process by selecting those candidates with the desired pharmacokinetic parameters. In one series of farnesyl protein transferase (FPT) inhibitors, gas chromatography with nitrogen-phosphorus detection (NPD) was initially used to analyze samples from pharmacokinetic studies in mice and monkeys. Typical turnaround times using this technique approached 2-4 weeks for method development, quantitation of study samples and calculation of pharmacokinetic parameters. Once LC-atmospheric pressure ionization (API) MS-MS analysis was implemented in these same studies, they could be completed in less than one week. The advantages of using LC-API-MS-MS to aid in the drug candidate selection process is demonstrated for one compound (SCH 44342) in this series of FPT inhibitors.
Bryant
M S
MS
Department of Drug Metabolism and Pharmacokinetics, Schering-Plough Research Institute, Kenilworth, NJ 07033, USA.
Korfmacher
W A
WA
Wang
S
S
Nardo
C
C
Nomeir
A A
AA
Lin
C C
CC
D000284:Administration, Oral; D019883:Alkyl and Aryl Transferases; D000818:Animals; D001552:Benzazepines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D002138:Calibration; D002849:Chromatography, Gas / Q000379:methods*; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D051231:Farnesyltranstransferase; D007275:Injections, Intravenous; D013058:Mass Spectrometry / Q000379:methods*; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics*; D014166:Transferases / Q000037:antagonists & inhibitors
D001552:Benzazepines; D004791:Enzyme Inhibitors; D010880:Piperidines; C097312:SCH 44342; D014166:Transferases; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase