The task of devel oping new diagnostic procedures and effective treat ments is

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 The task of devel oping new diagnostic procedures and effective treat ments is  Empty The task of devel oping new diagnostic procedures and effective treat ments is

Post  jy9202 on Wed Apr 02, 2014 7:21 am

The higher systemic exposure might in part be explained by the longer half life found in female BALB c mice in the present study. In this respect CR8 differs from both roscovitine and its close analogue N N1, which both have a reported half life of approximately 1 hour when given i. v. at the same dosage. CR8 was found [You must be registered and logged in to see this link.] to have approximately 100% oral bioavailability, which means the drug is suitable for oral route intake and that the first pass effect is negligible. CR8 distributed rapidly to all the peripheral tissues. The highest tissue distribution, as compared to plasma AUC, was found mainly in elimination organs, namely liver and kidneys, These results encour age the hope that CR8 could perhaps be used to treat liver and kidney tumors, since it was found to induce apoptotic cell death in both hepatic and renal tumor cell lines, Moreover, CR8 showed high distribution to the adipose tissue compared to that found in plasma, a factor that should be considered in dose scheduling in obese patients.

Surprisingly, CR8 showed higher distribution to the bone marrow compared to roscovitine, which was shown to pass the bone marrow barrier by only 1. 5% while the biodistribution of CR8 in the spleen was about 40%. Moreover, the cytotoxicity of CR8 against leukemic [You must be registered and logged in to see this link.] cell lines has been reported, Altogether, these results suggest the possible use of CR8 in treating leukemia and lymphomas. However, the high biodis tribution to the bone marrow may cause myelo suppression, which was not detected in roscovitine, Further studies are currently ongoing in our laboratory to explore the cytotoxic effect of CR8 on normal hematopoietic progenitors.

Moreover, we have observed five different metabolites with different polarities that have appeared with different kinetics throughout the CR8 kinetics. Urgent studies are needed to identify and quantify these metabolites, and to establish their pharmacological activates and toxicities. In the present study, we have [You must be registered and logged in to see this link.] also shown that CR8 passes the BBB compared to that reported for roscovitine, This exposure of the brain to CR8 is nevertheless higher than that required for inhibition of its neuronal targets like CDK5 and CK1, This fact may benefit the drug during further studies in neurodegenerative animal models and brain tumor models.

Conclusions We have developed and validated a simple, fast and se lective quantitative analytical method which allowed us to analyze the pharmacokinetic profile and tissue distri bution of the second generation CDK inhibitor CR8. CR8 was shown to have 100% bioavailability and longer half life compared to roscovitine, which may allow higher systemic exposure than the IC50 values for tumor cell death induction. The drug passes the BBB at a level sufficient to reach concentrations able to inhibit neur onal kinase targets.

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