Abstract
The effects of intravenous gefitinib (10 mg/kg), an anilinoquinazoline thymidylate kinase inhibitor (TKI), selective for the epidermal growth factor receptor (EGFR), on the urinary metabotypes of mice were studied. We hypothesized that, in response to the administration of gefitinib, there might be significant changes in the excretion of many endogenous metabolites in the urine, which could be correlated with the plasma pharmacokinetics (PK) of the drug. In order to investigate this conjecture, urine from male C57 BL6 mice was collected before IV dosing (10 mg/kg) and at 0-3, 3-8, and 8-24 h post-dose. The samples were profiled by UPLC/IM/MS and compared with the profiles obtained from undosed control mice with the data analyzed using multivariate statistical analysis (MVA). This process identified changes in endogenous metabolites over time and these were compared with drug and drug metabolite PK and excretion. While the MVA of these UPLC/IM/MS data did indeed reveal time-related changes for endogenous metabolites that appeared to be linked to drug administration, this analysis did not highlight the presence of either the drug or its metabolites in urine. Endogenous metabolites affected by gefitinib administration were identified by comparison of mass spectral, retention time and ion mobility-derived collision cross section data (compared to authentic standards wherever possible). The changes in endogenous metabolites resulting from gefitinib administration showed both increases (e.g., tryptophan, taurocholic acid, and the dipeptide lysyl-arginine) and decreases (e.g., deoxyguanosine, 8-hydroxydeoxyguanosine, and asparaginyl-histidine) relative to the control animals. By 8-24 h, the post-dose concentrations of most metabolites had returned to near control values. From these studies, we conclude that changes in the amounts of endogenous metabolites excreted in the urine mirrored, to some extent, the plasma pharmacokinetics of the drug. This phenomenon is similar to pharmacodynamics, where the pharmacological effects are related to the drug concentrations, and by analogy, we have termed this effect "pharmacometabodynamics".