Enhanced cerebral uptake of receptor ligands by modulation of P-glycoprotein function in the blood-brain barrier

Low cerebral uptake of some therapeutic drugs can be enhanced by modulation of P-glycoprotein (P-gp), an ATP-driven drug efflux pump at the blood-brai n barrier (BBB). We investigated the possibility of increasing cerebral upt ake of the beta-adrenergic ligands S-1'-[F-18]-fluorocarazolol (FCAR) and [ C-11]-carazolol (CAR) in P-gp knockout mice (mdr1a (-/-)) and by modulation of P-gp with cyclosporin A (CsA) in rats. Specific and nonspecific binding of FCAR in the rat brain were doubled by CsA, while target/nontarget ratio s and clearance from plasma (area under curve (AUC)) were not affected. Cer ebral uptake of CAR in rats was much lower than FCAR and nonspecific. CsA i ncreased this uptake 5-6-fold, not only due to P-gp modulation in the BBB b ut also to a 2-fold higher plasma AUG. In the CNS of mdr1a (-/-) mice, upta ke of FCAR and CAR was, respectively, 2-fold and 3-fold higher than in mdr1 a (+/+) mice. These results indicate that the cerebral uptake of beta-adren oceptor ligands can be increased by administration of P-gp modulators such as CsA without affecting regional distribution in the brain. P-gp modulatio n could improve the count statistics in PET studies of the CNS. (C) 2000 Wi ley-Liss, Inc.