10/08/2010 - Role of transporters in drug ADME

ATP-Binding Cassette B1 Transports Seliciclib (R-Roscovitine), a Cyclin-Dependent Kinase Inhibitor

Zsuzsanna Rajnai, Dóra Méhn, Erzsébet Beéry, Alper Okyar, Márton Jani, Gábor K. Tóth, Ferenc Fülöp, Francis Lévi and Peter Krajcsi

Drug Metab Dispos. 2010 Nov;38(11):2000-6. Epub 2010 Aug 10.


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 ATP-binding cassette B1 (ABCB1) because 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 treatment strategies using seliciclib are designed.

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