A Convenient Strategy for Quantitative Determination of Drug Concentrations in Tissue Homogenates Using a Liquid Chromatography/Tandem Mass Spectrometry Assay for Plasma Samples

Quantitativedeterminationofdrugconcentrationsintissuehomogenatesvialiquid chromatographytandem mass spectrometry (LC-MS/MS) is commonly conducted using the standards and analytical quality controls (QCs) prepared in the same matrix (tissue homo- genates),tokeepthematrixanditseffectsconsistentontheanalytesduringsampleextractionand analysis.Inthismanuscript,weproposedtoanalyzetissuehomogenatesamplesusinganLC-MS/ MS assay with the standards and analytical QCs prepared in plasma after tissue homogenate samples were appropriately diluted with plasma. BMS-650032 was used as a model compound, and its validated dog plasma assay was used for dog liver sample analyses. The tissue matrix effect wasevaluatedbydilutingliverhomogenateQCswithdrug-freeplasmaatdifferentdilutionfactors todeterminetheminimumrequireddilutionfactor(MRDF)atwhichtissuematrixhasinsignificantimpacttotheplasmaassay.The percentage deviation of the measured concentration from the nominal concentration was used as an indicator of the tissue matrix effect.Theresultssuggestedthatthetissuematrixeffectwasdecreasedastheplasmadilutionfactorincreased.Basedontheresultsof the tissue matrix effect evaluation, liver homogenate samples were analyzed after appropriate dilutions with plasma at the MRDF or greater dilution factors. The results confirmed that this approach generates accurate data, and the process is very convenient and economic. This approach has been used on the analyses of different tissues (liver and brain) and biofluid (bile) to support several drug development programs.