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Drug Metabolism & Disposition

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Influence of Hydroxyurea On Imatinib Mesylate (Gleevec) Transport at the Mouse Blood-Brain Barrier

Sébastien Bihorel, Gian Camenisch, Gerhard Gross, Michel Lemaire and Jean-Michel Scherrmann
Drug Metabolism and Disposition December 2006, 34 (12) 1945-1949; DOI: https://doi.org/10.1124/dmd.106.010975
Sébastien Bihorel
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Gian Camenisch
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Gerhard Gross
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Michel Lemaire
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Jean-Michel Scherrmann
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Abstract

The combination of imatinib mesylate and hydroxyurea provides a therapeutic benefit in patients with glioblastoma, although each drug is not effective when used alone. The increase of brain delivery of one or both drugs has been suggested to be a potential cause of this therapeutic benefit. The cross-influence of hydroxyurea and imatinib on their respective brain distribution was examined in mice and rats. We used in situ brain perfusion in mice to determine whether these two drugs have an influence on their respective initial transport across the blood-brain barrier. The brain penetration of hydroxyurea, assessed by its brain uptake clearance, Knet, was low in mice (∼0.10 μl/g/s) and not modified by coperfusion of imatinib (0.5–500 μM). Likewise, the brain penetration of imatinib was low (Knet, 1.39 ± 0.17 μl/g/s) and not modified by direct coperfusion of hydroxyurea (0.2–1000 μM) or by intravenous pretreatment with 15 or 1000 mg/kg hydroxyurea. We also examined a potential time-dependent influence of hydroxyurea on imatinib brain distribution after sustained subcutaneous administration in rats using an implantable osmotic pump. The brain penetration of imatinib in rats increased with time, ∼1.6-fold (p < 0.01) after 7 and 14 days' infusion of imatinib (3 mg/day) with or without hydroxyurea (15 mg/day), and was not influenced by hydroxyurea. The results of these two sets of experiments indicate that hydroxyurea has no significant influence on the brain distribution of imatinib in mice and rats.

Footnotes

  • This project was supported by Novartis Pharma AG contract (Novartis-INSERM n° 03035A10).

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

  • doi:10.1124/dmd.106.010975.

  • ABBREVIATIONS: GBM, glioblastoma; BBB, blood-brain barrier; Bcrp1, breast cancer resistance protein 1; EIAED, enzyme-inducing antiepileptic drug; Knet, brain uptake clearance; Kp, brain-to-blood concentration ratio at steady state; P-gp, P-glycoprotein.

    • Received May 5, 2006.
    • Accepted August 23, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 34 (12)
Drug Metabolism and Disposition
Vol. 34, Issue 12
1 Dec 2006
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OtherShort Communication

Influence of Hydroxyurea On Imatinib Mesylate (Gleevec) Transport at the Mouse Blood-Brain Barrier

Sébastien Bihorel, Gian Camenisch, Gerhard Gross, Michel Lemaire and Jean-Michel Scherrmann
Drug Metabolism and Disposition December 1, 2006, 34 (12) 1945-1949; DOI: https://doi.org/10.1124/dmd.106.010975

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Influence of Hydroxyurea On Imatinib Mesylate (Gleevec) Transport at the Mouse Blood-Brain Barrier

Sébastien Bihorel, Gian Camenisch, Gerhard Gross, Michel Lemaire and Jean-Michel Scherrmann
Drug Metabolism and Disposition December 1, 2006, 34 (12) 1945-1949; DOI: https://doi.org/10.1124/dmd.106.010975
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