Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

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 Friend leukemia virus strain B mice: wild-type, Mdr1a/b(2/2), Bcrp1(2/2), and Mdr1a/b(2/2)Bcrp1(2/2) 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(2/2)Bcrp1(2/2) 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.

Raltegravir Permeability across Blood-Tissue Barriers and the Potential Role of Drug Efflux Transporters

“…However, in the presence of both the P-gp and Bcrp inhibitors, the raltegravir P eff increased significantly in both the jejunum and ileum segments, suggesting a cooperative activity of these transporters in restricting raltegravir intestinal permeability. The cooperative function of P-gp and Bcrp transporters in the brain accumulation of the anticancer drug sunitinib was reported previously (45). In addition, previous studies have reported that raltegravir accumulation and permeability in Caco-2 cells are dependent on intestinal lumen pH (41,46), suggesting that the oral absorption of raltegravir might be altered by changes in luminal pH, as well as the expression and/or activity of the drug efflux transporters at the blood-intestinal barrier.…”

Synthetic miR-145 Mimic Enhances the Cytotoxic Effect of the Antiangiogenic Drug Sunitinib in Glioblastoma

“…Rajneet et al found that 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 of P-gp and Bcrp [40]. Therefore, our study provides a novel insight in improving Suntinib efficacy with genetic manipulation.…”

Cyclosporine-inhibitable Cerebral Drug Transport Does Not Influence Clinical Methadone Pharmacodynamics: Erratum

“…Many drugs are substrates for more than one efflux transporter, and several murine studies have shown that for these poly-transporter substrates, selective chemical inhibition or genetic knock-out of only one transporter has minimal effect on brain accumulation, but simultaneous inhibition or genetic knock-out of all members of the relevant transporter suite markedly increases brain biodistribution. [36][37][38] Thus, because BBB efflux transporters work in concert, unless cyclosporine were to inhibit all BBB transporters responsible for methadone efflux (assuming methadone is actually an efflux transporter substrate in vivo), inhibiting less than the full efflux transporter suite might not alter methadone pharmacodynamics. Therefore, the present results do not exclude the possibility that methadone is a substrate for one or more (non-cyclosporine inhibitable) efflux transporters at the human BBB.…”