The study objective was to investigate factors that affect the central nervous system (CNS) distribution of
elacridar.
Elacridar inhibits transport mediated by
P-glycoprotein (P-gp) and
breast cancer resistance
protein (Bcrp) and has been used to study the influence of transporters on brain distribution of chemotherapeutics. Adequate distribution of
elacridar across the blood-brain barrier (BBB) and into the brain parenchyma is necessary to target
tumor cells in the brain that overexpress transporters and reside behind an intact BBB. We examined the role of P-gp and Bcrp on brain penetration of
elacridar using Friend
leukemia virus strain B wild-type, Mdr1a/b(-/-), Bcrp1(-/-), and Mdr1a/b(-/-)Bcrp1(-/-) mice. Initially, the mice were administered 2.5 mg/kg of
elacridar intravenously, and the plasma and brain concentrations were determined. The brain-to-plasma partition coefficient of
elacridar in the wild-type mice was 0.82, as compared with 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 (Emax) at the highest dose were not significantly different in all genotypes. However, the ED50 was lower for Mdr1a/b(-/-) mice compared with Bcrp1(-/-) mice. These findings correlate with 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 an adjuvant
therapy to improve targeting of chemotherapeutic agents to
tumor cells in the brain parenchyma.