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Saturable active efflux by P-gp and Bcrp at the blood-brain barrier leads to non-linear distribution of elacridar to the central nervous system.

J Pharmacol Exp Ther. 2013 Feb 8;

Authors: Sane R, Agarwal S, Mittapalli RK, Elmquist W


The study objective was to investigate factors that affect the CNS distribution of elacridar. Elacridar inhibits P-gp and Bcrp mediated transport and has been used to study the influence of transporters on brain distribution of chemotherapeutics. Adequate distribution of elacridar across the BBB and into the brain parenchyma is necessary to target tumor cells in the brain that over-express transporters and reside behind an intact BBB. We examined the role of P-gp and Bcrp on brain penetration of elacridar using FVB wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice. Initially, mice were administered 2.5 mg/kg elacridar intravenously, and plasma and brain concentrations were determined. The brain-to-plasma partition coefficient of elacridar in wild-type mice was 0.82, as compared to 3.5 in Mdr1a/b(-/-) mice, 6.6 in Bcrp1(-/-) mice and 15 in Mdr1a/b(-/-)Bcrp1(-/-) mice, indicating that both P-gp and Bcrp limit the brain distribution of elacridar. The four genotypes were then administered increasing doses of elacridar and the CNS distribution of elacridar was determined. The observed and model predicted maximum brain-to-plasma ratios (E(max)) at the highest dose were not significantly different in all genotypes. However, the ED(50) was lower for Mdr1a/b(-/-) mice compared to Bcrp1(-/-) mice. These findings correlate to the relative expression of P-gp and Bcrp at the BBB in these mice and demonstrate the quantitative enhancement in elacridar CNS distribution as a function of its dose. Overall, this study provides useful concepts for future applications of elacridar as adjuvant therapy to improve targeting of chemotherapeutic agents to tumor cells in the brain parenchyma.

PMID: 23397054 [PubMed - as supplied by publisher]