Director Omics Waters Corporation - Milford, MA, Massachusetts, United States
Gefitinb, an anilinoquinazoline inhibitor of thymidylate kinase (selective for the epidermal growth factor receptor (EGFR)), was originally developed as a treatment for non-small cell lung cancer. In this study Male C57 BL6 mice were dosed IV with gefitinb (10 mg/kg) and then microsampling combined with a rapid (sub 5 min) UHPLC/qqqMS used to determine the pharmacokinetics of the drug and its major circulating metabolites. In addition, 10 circulating metabolites of the drug and 15 present in the urine were characterized using UHPLC/IM/HRMS. The addition of an IM separation gave rise to much improved MS data thereby aiding the identification of several novel glucuronide metabolites. As well as the drug and its metabolites untargeted metabolic phenotyping (metabonomics/metabolomics) enabled a range of time-related effects of the drug on endogenous metabolism to be detected. Changes in endogenous metabolite profiles, both increases and decreases in amounts, appeared shortly after dosing and had largely returned to their predose values by 24hrs. The changes in the amounts of endogenous metabolites excreted in the urine mirrored to some extent the plasma pharmacokinetics of the drug demonstrating a possible pharmacometabodynamic effect. This type of combined drug and endogenous metabolite profiling may this represent a method for better understanding the pharmacology of drugs in terms of the way that their effects modulate the metabolic pathways of the organisms exposed to them, including patients.
