Murine Central Nervous System and Bone Marrow Distribution of the Aurora A Kinase Inhibitor Alisertib: Pharmacokinetics and Exposure at the Sites of Efficacy and Toxicity
| Autor: | Ju-Hee, Oh, Erica A, Power, Wenjuan, Zhang, David J, Daniels, William F, Elmquist |
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| Rok vydání: | 2022 |
| Předmět: |
Central Nervous System
Mice Knockout Pharmacology ATP Binding Cassette Transporter Subfamily B Brain Neoplasms Azepines Neoplasm Proteins Mice Bone Marrow Animals ATP Binding Cassette Transporter Subfamily G Member 2 Molecular Medicine ATP Binding Cassette Transporter Subfamily B Member 1 Protein Kinase Inhibitors Aurora Kinase A |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 383:44-55 |
| ISSN: | 1521-0103 0022-3565 |
| Popis: | Important challenges in developing drugs that target central nervous system (CNS) tumors include overcoming barriers for CNS delivery and reducing systemic side effects. Alisertib, an aurora A kinase inhibitor, has been examined for treatment of several CNS tumors in preclinical and clinical studies. In this study, we investigated the distribution of alisertib into the CNS, the site of efficacy for brain tumors, and into the bone marrow, the site of dose-limiting toxicity leading to myelosuppression. Mechanisms influencing site-specific distribution, such as active transport mediated by the efflux proteins, p-glycoprotein (P-gp) and breast cancer resistance protein (Bcrp), were examined. Alisertib exposure to the brain in wild-type mice was less than 1% of that in the plasma, and was evenly distributed throughout various brain regions and the spinal cord. Studies using transporter knockout mice and pharmacological inhibition show that alisertib CNS distribution is influenced by P-gp, but not Bcrp. Conversely, upon systemic administration, alisertib distribution to the bone marrow occurred rapidly, was not significantly limited by efflux transporters, and reached higher concentrations than in the CNS. This study demonstrates that, given an equivalent distributional driving force exposure in plasma, the exposure of alisertib in the brain is significantly less than that in the bone marrow, suggesting that targeted delivery may be necessary to guarantee therapeutic efficacy with minimal risk for adverse events.Therefore, these data suggest that, to improve the therapeutic index when using alisertib for brain tumors, a localized regional delivery, such as convection-enhanced delivery, may be warranted. SIGNIFICANCE STATEMENT: The CNS penetration of alisertib is limited with uniform distribution in various regions of the brain, and P-gp efflux is an important mechanism limiting that CNS distribution. Alisertib rapidly distributes into the bone marrow, a site of toxicity, with a greater exposure than in the CNS, a possible site of efficacy. These results suggest a need to design localized delivery strategies to improve the CNS exposure of alisertib and limit systemic toxicities in the treatment of brain tumors. |
| Databáze: | OpenAIRE |
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