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.
Pucci
Vincenzo
V
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
Bonelli
Fabio
F
Monteagudo
Edith
E
Laufer
Ralph
R
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