Abstract
Seliciclib, a cyclin-dependent kinase inhibitor is a promising candidate to treat a variety of cancers. Pharmacokinetic studies have shown high oral bioavailability but limited brain exposure to the drug. Seliciclib, a cyclin-dependent kinase inhibitor is a promising candidate to treat a variety of cancers. Pharmacokinetic studies have shown high oral bioavailability but limited brain exposure to the drug. This study shows that seliciclib is a high affinity substrate of ABCB1 as it activates the ATPase activity of the transporter with an EC50 of 4.2 μM and shows vectorial transport in MDCKII-MDR1 cells yielding an efflux ratio of 8. This interaction may be behind the drug's limited penetration of the blood-brain barrier. ABCB1 overexpression on the other hand does not confer resistance to the drug in the models tested. These findings should be considered when designing treatment strategies utilizing seliciclib.
- ABC transporters
- active transport
- blood-brain barrier
- blood-CNS transport
- cellular transport
- CNS pharmacokinetics
- multi-drug resistance
Footnotes
- The American Society for Pharmacology and Experimental Therapeutics