RT Journal Article
SR Electronic
T1 A Simple Liquid Chromatography-Tandem Mass Spectrometry Method to Determine Relative Plasma Exposures of Drug Metabolites across Species for Metabolite Safety Assessments (Metabolites in Safety Testing). II. Application to Unstable Metabolites
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1290
OP 1296
DO 10.1124/dmd.112.044552
VO 40
IS 7
A1 Gao, Hongying
A1 Obach, R. Scott
YR 2012
UL http://dmd.aspetjournals.org/content/40/7/1290.abstract
AB We previously described a simple liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to determine relative plasma exposures of drug metabolites across species for metabolite safety assessments. It offers time- and resource-sparing advantages to ascertain metabolite exposure comparisons between humans and laboratory animal species for stable metabolites with high confidence. In this study, we tested the limitation of the methodology with compounds possessing six substituents found in unstable metabolites. Stabilization procedures were used, and stabilized samples were compared with untreated samples for structures with established stabilization processes. In most cases, the parent compounds with established stability were used as the intrinsic stability references except in cases in which the metabolite was more stable than the parent compound. Long-term storage stability of the unstable structures was tested by comparing the response ratio of the metabolite to the stability reference compound for multiple independent analyses covering the storage duration. Autosampler stability was tested using the same response ratio of the reinjections of the reconstituted solution overnight over the first injections. The results supported that the possibility that an abbreviated LC-MS/MS peak area ratio comparison can be applied to epoxide, amide, catechol, and acyl glucuronides to determine the relative plasma exposure of drug metabolites across species; but it may not be suitable for iminium ions and esters. Stability of suspected unstable metabolites can be tested using the methodology described above.