Abstract

This study quantitatively assessed transport mechanisms that limit the brain distribution of sunitinib, and investigated adjuvant strategies to improve its brain delivery for the treatment of glioblastoma multiforme (GBM). Sunitinib has not shown significant activity in GBM clinical trials, despite positive results seen in preclinical xenograft studies. We performed in vivo studies in transgenic FVB mice: wild-type, Mdr1a/b(-/-), Bcrp1(-/-) and Mdr1a/b(-/-)Bcrp1(-/-) genotypes were examined. The brain-to-plasma AUC ratio after an oral dose (20 mg/kg) was similar to steady-state tissue distribution coefficient (Kp), indicating linear distribution kinetics in mice over this concentration range. Furthermore, the distribution of sunitinib to the brain increased after administration of selective P-glycoprotein (P-gp) or breast cancer resistance protein (Bcrp) pharmacological inhibitors, and a dual inhibitor, elacridar, comparable to that of the corresponding transgenic genotype. The brain-to-plasma ratio after co-administration of elacridar in wild-type was ~12, compared to ~17.3 in Mdr1a/b(-/-)Bcrp1(-/-) mice. Overall, these findings indicate that there is a co-operation at the BBB in restricting the brain penetration of sunitinib and brain delivery can be enhanced by administration of a dual inhibitor. These data indicate that the presence of cooperative efflux transporters, P-gp and Bcrp, in an intact BBB, can protect invasive glioma cells from chemotherapy. Thus, one may consider the use transporter inhibition as a powerful adjuvant in the design of future clinical trials for the targeted delivery of sunitinib to GBM.