Restricted brain penetration of the tyrosine kinase inhibitor erlotinib due to the drug transporters P-gp and BCRP

Summary Purpose Erlotinib (Tarceva®, OSI-774) is a small molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase. As high-grade gliomas frequently show amplification, overexpression and/or mutation of EGFR, this drug has been tested in several clinical trials with glioblastoma patients, but unfortunately, with little success. As erlotinib is a known substrate of P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP) we have investigated the effect of these ABC-transporters on the brain penetration of erlotinib. Study design Erlotinib (50 mg/kg) was given by i.p. administration to wild-type (WT), Mdr1ab -/- (single P-gp knockout), Bcrp1 -/- (single Bcrp1 knockout) and Mdr1ab -/- Bcrp1 -/- (compound P-gp and Bcrp1 knockout) mice. Drug levels in plasma and tissues were determined by reversed-phase high-performance liquid chromatography. Results Relative to Mdr1ab -/- Bcrp1 -/- mice that are deficient for both drug transporters, the area under the concentration time curve in brain tissue (AUC) brain of erlotinib decreased significantly by 1.6-fold in Mdr1ab -/- mice where Bcrp1 is present (49.6 ± 3.95 versus 31.1 ± 1.7, μg/g*h; P