A direct technique for the simultaneous determination of 10 drug candidates in plasma by liquid chromatography-atmospheric pressure chemical ionization mass spectrometry interfaced to a Prospekt solid-phase extraction system.
New drug candidates are being synthesized at an ever increasing rate and, until recently, the pharmacokinetics of only a few of these could be evaluated. Our laboratory is taking a novel approach to rapid multiple pharmacokinetic screening of potential drug candidates in which mixtures of new substances are co-administered to animals and analyzed simultaneously in plasma using liquid chromatography with tandem MS/MS detection in conjunction with a Prospekt automated on-line solid-phase extraction system. Plasma is sampled via an autosampler and extracted by the Prospekt with the eluent being introduced directly via a reverse phase HPLC column and a heated nebulizer interface to the mass spectrometer. Generic extraction and chromatographic conditions generally give good recoveries. The chromatographic run-times are less than 8 min. The accuracy and precision of these assays are carefully controlled with recoveries generally in the range 80-120% and coefficients of variation less than 20%. Lower quantifiable limits range from 2.5 to 5 ng ml-1. This approach considerably reduces the number of animals needed to screen drug candidates and its power is illustrated by determination of the pharmacokinetics of 10 substances after their simultaneous administration to dogs.
McLoughlin
D A
DA
Department of Drug Metabolism, Merck Research Laboratories, West Point, PA 19486, USA.
Olah
T V
TV
Gilbert
J D
JD
D000818:Animals; D001274:Atmospheric Pressure; D001322:Autoanalysis / Q000295:instrumentation*; D002853:Chromatography, Liquid / Q000379:methods*; D004285:Dogs; D008297:Male; D013058:Mass Spectrometry / Q000379:methods*; D009862:Online Systems; D004364:Pharmaceutical Preparations / Q000032:analysis*; D011786:Quality Control; D015203:Reproducibility of Results
D004364:Pharmaceutical Preparations