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. VSports手机版.

Study design: Erlotinib (50 mg/kg) was given by i. p V体育安卓版. 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 V体育ios版. 7, μg/g*h; P < 0. 01). In Bcrp1(-/-) mice, were P-gp is present, a more pronounced 3. 8-fold decrease to 13. 0 ± 0. 70, μg/g*h (P < 0. 01) was observed, which is close to the 4. 5-fold decrease in the AUC(brain) of erlotinib found in WT mice where both drug transporters are present (11. 0 ± 1. 35, P < 0. 01). The plasma clearance of erlotinib was similar in mice deficient for P-gp and/or Bcrp1 compared with wild-type mice. In all other tissues the differences between the genotypes were negligible. .

Conclusions: Both P-gp and Bcrp1 reduce the brain penetration of erlotinib. Although P-gp appears to be the most effective factor limiting the brain penetration of erlotinib, the highest brain accumulation was observed when Bcrp1 was also absent. Strategies to inhibit P-gp/BCRP in patients to improve delivery of (novel molecular-targeted) substrate agents, such as erlotinib, to the brain may be required for treatment of intracranial malignancies. VSports最新版本.