Received for publication May 12, 2006.
Revised August 2, 2006.
Accepted for publication August 23, 2006.

Influence of hydroxyurea on imatinib mesylate transport at the mouse blood-brain barrier

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 K_net, was low in mice (~ 0.10 µL/g/s) and not modified by co-perfusion of imatinib (0.5-500 µM). Likewise, the brain penetration of imatinib was low (K_net, 1.39 ± 0.17 µL/g/s) and not modified by direct co-perfusion of hydroxyurea (0.2-1000 µM) or by intravenous pre-treatment 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) following 7 and 14 days infusion of imatinib (3 mg/day) with or without hydroxyurea (15 mg/d), 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.

Key words: ABC transporters, blood-brain barrier, drug distribution, p-glycoprotein, pharmacokinetics