Detection of Pharmacolipidodynamic Effects Following the Intravenous and Oral Administration of Gefitinib to C57Bl/6JRj Mice by Rapid UHPLC/MS Analysis of Plasma

Abstract

Abstract Omics based biomarker technologies including metabolic profiling ( metabolomics /metabonomics) and lipidomics are making a significant impact on disease understanding, drug development, and translational research. A wide range of patho-physiological processes involve lipids, monitoring changes in lipid concentration can give valuable insights into drug toxicity and off target pharmacology. Here we report changes in plasma lipid profiles of male C57Bl/6JRj mice following the PO and IV administration of the TKI inhibitor gefitinib were studied using untargeted LC/MS. Statistical analysis the data obtained for both the IV and PO samples showed time-related changes in the amounts of lipids from a number of classes affected. The largest changes were associated with a rapid onset of these changes following gefitinib administration followed by a gradual returning to the type of profiles seen for predose samples by 24 h post dose. Investigation of the lipids responsible for the variance observed in the data showed that GPE, GPI, GPA, PC and LPC were subject to the largest disruption with both transient increases and decreases in relative amounts seen in response to administration of the drug. The pattern of the changes in the relative amounts of the lipids subject to change appeared to correlate with the pharmacokinetics of gefitinib (and its major metabolites) and supports the concept of a distinct pharmacometabodynamic relationship