COMPLETE IN-VIVO REVERSAL OF P-GLYCOPROTEIN PUMP FUNCTION IN THE BLOOD-BRAIN-BARRIER VISUALIZED WITH POSITRON-EMISSION-TOMOGRAPHY

1 Homozygously mdr1a gene disrupted mice (mdr1a(-/-) mice) and wild ty pe mice (mdr1a(+/+) mice) were used to develop a method for P-glycopro tein (P-gp) function imaging non-invasively and to study the effect of a P-gp reversal agent on its function in vivo. 2 [C-11]verapamil (0.1 mg/kg) was administered and the changes in tissue concentrations were determined ex vivo by organ extirpation and in viva with PET. To bloc k P-gp function, cyclosporin A was administered. 3 Biodistribution stu dies revealed 9.5-fold (P<0.001) and 3.4-fold (P<0.001) higher [C-11]v erapamil in the brain and testes of mdr1a(-/-) mice than in mdr1a(+/+) mice. Cyclosporin A (25 mg/kg) increased [C-11]verapamil levels in th e brain and testes of mdr1a(+/+) mice in both cases 3.3-fold (P<0.01 ( brain); P<0.001 (testes)). Fifty mg/kg cyclosporin A increased [C-11]v erapamil in the brain 10.6-fold (P<0.01) and in the testes 4.1-fold (P <0.001). No increases were found in the mdr1a(-/-) mice. This indicate s complete inhibition of P-gp mediated [C-11]verapamil efflux. 4 Posit ron camera data showed lower [C-11]verapamil levels in the brain of md r1a(+/+) mice compared to those in mdr1a(-/-) mice. [C-11]verapamil ac cumulation in the brain of mdr1a(+/+) mice was increased by cyclospori n A to levels comparable with those in mdr1a(-/-) mice, indicating tha t reversal of P-gp mediated efflux can be monitored by PET. 5 We concl ude that cyclosporin A can fully block the P-gp function in the blood brain barrier and the testes and that PET enables the in viva measurem ent of P-gp function and reversal of its function noninvasively.