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

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de Vries NA, Buckle T, Zhao J, Beijnen JH, Schellens JH, van Tellingen O

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

Invest New Drugs. 2012 Apr;30(2):443-9. doi: 10.1007/s10637-010-9569-1. Epub 2010 Oct 21.

PubMed ID

20963470 [ View in PubMed

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Abstract

PURPOSE: Erlotinib (Tarceva(R), 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, mug/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, mug/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.

DrugBank Data that Cites this Article

Drug Transporters

Drug	Transporter	Kind	Organism	Pharmacological Action	Actions
Erlotinib	P-glycoprotein 1	Protein	Humans	Unknown	Substrate Inhibitor	Details