Abstract
The knowledge of the brain permeation properties of drugs acting at the brain level is particularly important in the early phase of development and before clinical development. JLK1486 is a new anticancer drug recently reported, which in vitro evaluation on glioma cell lines is particularly promising. We reported here the HPLC analysis of cerebrospinal fluid (CSF) samples of rat injected by JLK1486. Only 0.23% of the total JLK1486 injected was found in CSF, indicating that only small amount of the drug cross the BBB, while theoretical calculations predict for this drug a high capacity of permeation. A possible hypothesis is the rapid metabolism of JLK1486 into conjugate metabolites. Relative to the possible interaction between JLK1486 and P-glycoprotein (P-gp), an ATPase assay was performed allowing to conclude that JLK1486 drug is not a good substrate for P-gp ATPase. In vivo experiments on transgenic mice brain xenografted by glioblastoma cells actually underway are required in order to confirm the in vivo antiproliferative properties of JLK1486 on glioblastoma.
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Abbreviations
- AUC:
-
Areas under concentrations curves
- BBB:
-
Blood brain barrier
- CSF:
-
Cerebrospinal fluid
- DA:
-
Dopamine
- DOPAC:
-
Dihydroxphenyl acetic acid
- MDR:
-
Multidrug-resistant
- P-gp:
-
P-glycoprotein
- TMZ:
-
Temozolomide
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Acknowledgments
The authors wish to thank M. Nicolas and B. Zouani (Institut de medicine navale du service des armées, Toulon, France) for helpful contribution to this study. IBDML-CNRS (Institut de Biologie du Developpement de Marseille Luminy, France) is gratefully acknowledged for financial support.
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Barthelemy-Requin, M., Nugier, J., Madonna, S. et al. Blood–brain barrier permeability and transport studies of JLK1486: a new antiglioblastoma drug. Med Chem Res 21, 1334–1340 (2012). https://doi.org/10.1007/s00044-011-9649-6
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DOI: https://doi.org/10.1007/s00044-011-9649-6