Influence of breast cancer resistance protein (Abcg2) and p-glycoprotein (Abcb1a) on the transport of imatinib mesylate (Gleevec®) across the mouse blood-brain barrier

• Published in: Journal of neurochemistry 2007-09, Vol.102 (6), p.1749-1757
• Main Authors: Bihorel, Sébastien, Camenisch, Gian, Lemaire, Michel, Scherrmann, Jean-Michel
• Format: Article
• Language: English
• Subjects: Acridines - pharmacology; Animals; Antineoplastic Agents - metabolism; ATP Binding Cassette Transporter, Subfamily B - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B - genetics; ATP Binding Cassette Transporter, Subfamily B - metabolism; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters - antagonists & inhibitors; ATP-Binding Cassette Transporters - genetics; ATP-Binding Cassette Transporters - metabolism; Benzamides; Biochemistry; Biological and medical sciences; Biological Transport, Active - drug effects; Biological Transport, Active - physiology; blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Brain - blood supply; Brain - drug effects; Brain - metabolism; Breast cancer; breast cancer resistance protein; CGP74588; Cyclosporins - pharmacology; Dibenzocycloheptenes - pharmacology; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Glycoproteins; Gynecology. Andrology. Obstetrics; imatinib; Imatinib Mesylate; Immunosuppressive Agents - pharmacology; Inhibitor drugs; Male; Mammary gland diseases; Medical sciences; Mice; Mice, Knockout; mouse; Neurology; Neurosciences; p-glycoprotein; Piperazines - metabolism; Piperazines - pharmacokinetics; Proteins; Pyrimidines - metabolism; Pyrimidines - pharmacokinetics; Quinolines - pharmacology; Rodents; Tetrahydroisoquinolines - pharmacology; Tumors; Tumors of the nervous system. Phacomatoses
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2007.04808.x

Imatinib, a protein tyrosine kinase inhibitor, may prevent the growth of glioblastoma cells. Unfortunately, its brain distribution is restricted by p-glycoprotein (p-gp or multidrug resistance protein Mdr1a), and probably by breast cancer resistance protein (Bcrp1), two efflux pumps expressed at the blood-brain barrier (BBB). We have used in situ brain perfusion to investigate the mechanisms of imatinib transport across the mouse BBB. The brain uptake of imatinib in wild-type mice was limited by saturable efflux processes. The inhibition of p-gp, by valspodar and zosuquidar, increased imatinib uptake (2.5-fold), as did the deficiency of p-gp in Mdr1a/1b(-/-) mice (5.5-fold). Perfusing imatinib with the p-gp/Bcrp1 inhibitor, elacridar, enhanced the brain uptake of imatinib in wild-type (4.1-fold) and Mdr1a/1b(-/-) mice (1.2-fold). However, the brain uptake of imatinib was similar in wild-type and Bcrp1(-/-) mice when it was perfused at a non-saturating concentration. The brain uptake of CGP74588, an active metabolite of imatinib, was low. It was increased by perfusion with elacridar (twofold), but not with valspodar and zosuquidar. CGP74588 uptake was 1.5 times greater in Bcrp1(-/-) mice than in wild-type mice. These data suggest that imatinib transport at the mouse BBB is limited by p-gp and probably by Bcrp1, and that CGP74588 transport is restricted by Bcrp1.