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Updated: May 25, 2026
Systemic and Local Drug Delivery for Treating Diseases of the Central Nervous System in Rodent Models
Published on: August 16, 2010
Brain distribution of cediranib is limited by active efflux at the blood-brain barrier
Tianli Wang1, Sagar Agarwal, William F Elmquist
1Department of Pharmaceutics and Brain Barriers Research Center, University of Minnesota, Minneapolis, Minnesota, USA.
Abstract:
Cediranib is an orally active tyrosine kinase inhibitor that targets the vascular endothelial growth factor receptor family. Because of its potent antiangiogenic and antitumor activities, cediranib has been evaluated for therapy in glioma, a primary brain tumor. This study investigated the influence of two important efflux transporters at the blood-brain barrier, P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), on the delivery of cediranib to the central nervous system. In vitro studies indicated that cediranib is a dual substrate for both P-gp and Bcrp. It is noteworthy that in spite of the in vitro data the in vivo mouse disposition studies conclusively showed that P-gp was the dominant transporter restricting the brain distribution of cediranib. The brain-to-plasma partitioning (AUC(brain)/AUC(plasma), where AUC is area under the curve) and the steady-state brain-to-plasma concentration ratio of cediranib were approximately 20-fold higher in Mdr1a/b⁻/⁻ and Mdr1a/b⁻/⁻Bcrp1⁻/⁻ mice compared with wild-type and Bcrp1⁻/⁻ mice. Moreover, there was no significant difference in brain distribution of cediranib between wild-type and Bcrp1⁻/⁻ mice and between Mdr1a/b⁻/⁻ and Mdr1a/b⁻/⁻Bcrp1⁻/⁻ mice. These results show that, unlike other tyrosine kinase inhibitors that are dual substrates for P-gp and Bcrp, Bcrp does not restrict the distribution of cediranib across the blood-brain barrier. We also show that inhibition of P-gp using specific or nonspecific inhibitors resulted in significantly enhanced delivery of cediranib to the brain. Concurrent administration of cediranib with chemical modulators of efflux transporters can be used as a strategy to enhance delivery and thus efficacy of cediranib in the brain. These findings are clinically relevant to the efficacy of cediranib chemotherapy in glioma.
Insights
P-glycoprotein (P-gp) significantly restricts cediranib brain delivery, while breast cancer resistance protein (Bcrp) does not. Inhibiting P-gp enhances cediranib brain penetration, suggesting a strategy to improve glioma treatment efficacy.
Area of Science:
- Pharmacology
- Neuroscience
- Oncology
Background:
- Cediranib is an orally active tyrosine kinase inhibitor targeting VEGFR, investigated for glioma therapy due to its antiangiogenic and antitumor effects.
- The blood-brain barrier (BBB) limits central nervous system drug delivery, with efflux transporters like P-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp) playing a key role.
- Understanding transporter interactions is crucial for optimizing cediranib's efficacy in treating brain tumors like glioma.
Purpose of the Study:
- To investigate the impact of P-gp and Bcrp on cediranib's delivery into the central nervous system.
- To determine the dominant efflux transporter restricting cediranib's brain distribution.
- To explore strategies for enhancing cediranib brain penetration.
Main Methods:
- In vitro assessment of cediranib as a substrate for P-gp and Bcrp.
- In vivo mouse disposition studies using wild-type, Bcrp1⁻/⁻, Mdr1a/b⁻/⁻, and Mdr1a/b⁻/⁻Bcrp1⁻/⁻ mice.
- Evaluation of cediranib brain-to-plasma partitioning and steady-state concentrations.
- Assessment of brain delivery following P-gp inhibition.
Main Results:
- In vitro studies showed cediranib is a dual substrate for P-gp and Bcrp.
- In vivo studies revealed P-gp as the primary transporter limiting cediranib brain distribution.
- Brain-to-plasma partitioning of cediranib was approximately 20-fold higher in mice lacking P-gp (Mdr1a/b⁻/⁻) compared to wild-type.
- No significant difference in brain distribution was observed between wild-type and Bcrp1⁻/⁻ mice, or between Mdr1a/b⁻/⁻ and Mdr1a/b⁻/⁻Bcrp1⁻/⁻ mice.
- Inhibition of P-gp significantly increased cediranib delivery to the brain.
Conclusions:
- P-gp, not Bcrp, is the dominant efflux transporter restricting cediranib's distribution across the blood-brain barrier.
- Inhibition of P-gp represents a viable strategy to enhance cediranib brain delivery and potentially improve therapeutic efficacy in glioma.
- Concurrent administration of cediranib with efflux transporter modulators could optimize chemotherapy for brain tumors.
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