(1034-C) Doing more with less: Application of microsampling, LC/MS/MS and MS imaging for the measurement of drug, metabolites and lipid biomarkers in biofluids and tissues
Tuesday, February 6, 2024
12:00 PM – 1:00 PM EST
Location: Exhibit Halls AB
Abstract: Understanding the fate and effect of a candidate pharmaceutical on a biological system is a key part of the drug discovery and development process. DMPK and biomarker studies can provide information on ADME, generation of potentially toxic metabolites, and dysregulation of metabolic processes. These studies form an essential part of the drug development package, often requiring multiple animal studies. In discovery limited animal studies are performed to support lead candidate selection, optimize exposure and identify metabolic soft spots. Despite these studies candidate drugs are still eliminated in preclinical and early clinical phases due to toxicity or undesirable DMPK properties.
The combination of the microsampling and the exquisite sensitivity of modern LC/MS/MS and MS imaging has the potential to rapidly produce significantly more information from these early drug discovery samples, improving the candidate selection process. To demonstrate this hypothesis, we applied targeted LC/MS/MS and MS imaging to the analysis of plasma, urine and liver samples derived from administration of gefitinib to C57Bl/6JRj mice. Rapid oral absorption resulted in peak plasma concentrations at 1 h of ca. 7 µg/mL, that declined with a half-life of 3.8h (2.6h for the IV route) providing an estimated oral bioavailability of 53%. Gefitinib itself was the major circulating drug-related compound in plasma extracts, with a total of 11 metabolites identified. Urine analysis identified 15 metabolites including two novel glucuronides. 433 Lipids were quantified in plasma and liver extracts showed glycerophosethanolamine, glycosylphosphatidylinositol, phosphatidylcholines and lysophosphatidylcholines dysregulation following dosing. MS imaging of liver samples using targeted MRM allowed the visualization of the drug metabolites and lipid biomarkers. LPC signals were elevated in both the plasma and liver samples whilst PC signals were reduced. This study demonstrates the potential of microsampling and modern MS techniques to extract latent information from early animal studies which could improve candidate selection.