Enhanced mass resolution method development, validation and assay application to support preclinical studies of a new drug candidate.
A very highly sensitive and highly selective liquid chromatographic/tandem mass spectrometric (LC/MS/MS) method was developed to evaluate and quantify a new drug candidate in different biological matrices. Following a simple plasma protein precipitation using acetonitrile, the post-treatment samples were analyzed on a C18 column interfaced with a new generation of triple-quadrupole mass spectrometer. The recently introduced triple-quadrupole mass spectrometer, the TSQ Quantum Ultra, with enhanced mass-resolution capability, demonstrated improved sensitivity (0.05 ng/mL), coupled with suitable accuracy and precision, over a broad linear dynamic range (0.05-1000 ng/mL). A comparison of the assay performance data (dynamic range, calibration curve equation, precision and accuracy) of the enhanced resolution method against a unit resolution method under optimized conditions showed the performance improvement of the enhanced mass resolution method for bioanalytical high-throughput applications. The enhanced mass resolution method herein described was successfully applied to the evaluation of the pharmacokinetic profile of a new drug candidate in rat, rabbit and dog plasma samples.
Department of Pharmacology, Istituto di Ricerche di Biologia Molecolare P. Angeletti (IRBM), Merck Sharp and Dohme Research Laboratories, Via Pontina km 30.600, 00040 Pomezia, Roma, Italy. vincenzo_pucci@merck.com
Vincenzo
V
Pucci
Fabio
F
Bonelli
Edith
E
Monteagudo
Ralph
R
Laufer
D000818:Animals; D001322:Autoanalysis; D001798:Blood Proteins / Q000032:analysis; D002138:Calibration; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D007202:Indicators and Reagents; D008297:Male; D013058:Mass Spectrometry; D004364:Pharmaceutical Preparations / Q000032:analysis*; D011786:Quality Control; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012015:Reference Standards; D015203:Reproducibility of Results
D001798:Blood Proteins; D007202:Indicators and Reagents; D004364:Pharmaceutical Preparations