title: Analytical approach to characterize the intratumoral pharmacokinetics and pharmacodynamics of gefitinib in a glioblastoma model.
abstract: Heterogeneity in brain tumors can result in variable drug distribution and possibly drug response; however, there are no readily accessible means to obtain regional pharmacokinetic (PK)/pharmacodynamic (PD) information in preclinical tumor models that typically rely on average drug concentration measurements. On the basis of a novel serial brain tumor sectioning protocol, sensitive and robust methods were developed to characterize the intratumoral PK [liquid chromatography with tandem mass spectrometry detection (LC/MS/MS)] and PD (phosphorylated extracellular-signal-regulated kinase, antibody-based detection) of gefitinib in small amounts of glioblastoma tumor samples obtained from mice bearing intracerebral tumors administered 150 mg/kg of gefitinib. LC/MS/MS method was accurate (±15%) and precise (coefficient of variation ≤15%). For PD analysis, two antibody-based assay systems [enzyme-linked immunosorbent assay and meso scale discovery (MSD)] were compared and the more sensitive method (MSD) was selected. Gefitinib concentrations showed up to 2.4 ± 0.7-fold intratumoral variability in PK and 1.5 ± 0.20-fold variability in PD. The methods are sufficiently accessible and could be applied to other anticancer drugs and tumor models to obtain greater resolution of intratumoral PKs and PDs.
authors.affiliation: Department of Pharmaceutical Sciences, Temple University, Philadelphia, Pennsylvania 19140, USA.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Sharma
authors.forename: Hua
authors.initials: H
authors.lastname: Lv
authors.forename: James M
authors.initials: JM
authors.lastname: Gallo
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000378:metabolism*; D002853:Chromatography, Liquid; D000077156:Gefitinib; D005909:Glioblastoma / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D011799:Quinazolines / Q000493:pharmacokinetics* / Q000494:pharmacology*; D053719:Tandem Mass Spectrometry
chemical_list: D000970:Antineoplastic Agents; D011799:Quinazolines; D000077156:Gefitinib