Scdt-19. Delivery of Ispinesib Is Limited by Efflux Transport at the Blood-brain Barrier (bbb)
Year: 2017
Type: article
Abstract: A challenge in developing therapies for GBM is the inability of drugs to cross the BBB. Ispinesib, an inhibitor of kinesin spindle protein, has potent anti-cancer activity by causing mitotic arrest and growth inhibition. The objective was to determine the distribution of ispinesib across the BBB, and determine mechanisms responsible for limiting brain delivery. Brain distribution studies were conducted in FVB wild-type (WT), triple-knockout (TKO; Mdr1a/b(-/-)Bcrp1(-/-)), P-gp knockout (PKO; Mdr1a/b(-/-)) and Bcrp knockout (BKO; Bcrp1(-/-)) mice. In a separate study, WT mice administered with and without elacridar (n=5) were co-dosed ispinesib. Plasma and brain were collected one-hour post dose. Brain distribution studies were conducted in WT and TKO mice, and plasma and brain were harvested at 7 time points. Rapid equilibrium dialysis assessed the unbound fractions of ispinesib in plasma and brain. All the samples were analyzed using LC-MS/MS. The single time point studies show that the brain concentrations in WT and BKO mice are significantly lower than in plasma, and brain-to-plasma ratios (B:P) in WT and BKO mice were below 2%. Brain concentrations in TKO and PKO mice are significantly higher than WT and BKO. The B:P was increased in the TKO and PKO mice [(WT: 0.0071 ± 0.01; BKO: 0.016 ± 0.01 (not significant); TKO: 0.35 ± 0.25 (p=0.0140); PKO: 0.54 ± 0.14 (p=0.0005)]. Plasma concentrations in WT and TKO mice following oral administration of ispinesib were about 33% of plasma concentrations following i.p. dosing and the B:P ratios were similar. Brain concentrations are less than 5% of plasma following elacridar co-administration, and did not cause a significant increase in ispinesib brain delivery. Brain delivery of ispinesib is restricted by active efflux transporters (P-gp). The pharmacokinetic studies in FVB mice post intravenous administration will confirm the findings from single time point studies.
Source: Neuro-Oncology
Institutions: University of Minnesota, Cleveland Clinic, Mayo Clinic in Florida
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767498151