Determination of exposure multiples of human metabolites for MIST assessment in preclinical safety species without using reference standards or radiolabeled compounds.
A simple, reliable, and accurate method was developed for quantitative assessment of metabolite coverage in preclinical safety species by mixing equal volumes of human plasma with blank plasma of animal species and vice versa followed by an analysis using high-resolution full-scan accurate mass spectrometry. This approach provided comparable results (within (±15%) to those obtained from regulated bioanalysis and did not require synthetic standards or radiolabeled compounds. In addition, both qualitative and quantitative data were obtained from a single LC-MS analysis on all metabolites and, therefore, the coverage of any metabolite of interest can be obtained.
Drug Metabolism and Pharmacokinetics, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.
Shuguang
S
Ma
Zhiling
Z
Li
Keun-Joong
KJ
Lee
Swapan K
SK
Chowdhury
D000818:Animals; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid / Q000592:standards; D006801:Humans; D007553:Isotope Labeling; D009570:Nitriles / Q000097:blood / Q000378:metabolism / Q000592:standards; D004364:Pharmaceutical Preparations / Q000097:blood / Q000378:metabolism* / Q000592:standards; D010879:Piperazines / Q000097:blood / Q000378:metabolism / Q000592:standards; D011817:Rabbits; D012015:Reference Standards; D053719:Tandem Mass Spectrometry / Q000592:standards; D018675:Toxicity Tests; D014508:Urea / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism / Q000592:standards
D009570:Nitriles; D004364:Pharmaceutical Preparations; D010879:Piperazines; C511125:SCH-A compound; D014508:Urea