PT  - JOURNAL ARTICLE
AU  - Rajneet K. Oberoi
AU  - Rajendar K. Mittapalli
AU  - William F. Elmquist
TI  - Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain
AID  - 10.1124/jpet.113.208959
DP  - 2013 Dec 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 755--764
VI  - 347
IP  - 3
4099  - http://jpet.aspetjournals.org/content/347/3/755.short
4100  - http://jpet.aspetjournals.org/content/347/3/755.full
SO  - J Pharmacol Exp Ther2013 Dec 01; 347
AB  - 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 Friend leukemia virus strain B mice: wild-type, Mdr1a/b(−/−), Bcrp1(−/−), and Mdr1a/b(−/−)Bcrp1(−/−) genotypes were examined. The brain-to-plasma area under the curve ratio after an oral dose (20 mg/kg) was similar to the steady-state tissue distribution coefficient, 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 coadministration of elacridar in wild-type mice was ∼12 compared with ∼17.3 in Mdr1a/b(−/−)Bcrp1(−/−) mice. Overall, these findings indicate that there is a cooperation at the blood-brain barrier (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 of transporter inhibition as a powerful adjuvant in the design of future clinical trials for the targeted delivery of sunitinib in GBM.