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

P. Doze, A. Van Waarde, P. H. Elsinga, N. H. Hendrikse, W. Vaalburg

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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-brain barrier (BBB). We investigated the possibility of increasing cerebral uptake of the β-adrenergic ligands S-1'-[18F]-fluorocarazolol (FCAR) and [11C]-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 ratios and clearance from plasma (area under curve (AUG)) were not affected. Cerebral uptake of CAR in rats was much lower than FCAR and nonspecific. CsA increased this uptake 5-6-fold, not only due to P-gp modulation in the BBB but also to a 2-fold higher plasma AUG. In the CNS of mdr1a (-/-) mice, uptake of FCAR and CAR was, respectively, 2-fold and 3-fold higher than in mdr1a (+/+) mice. These results indicate that the cerebral uptake of β- adrenoceptor ligands can be increased by administration of P-gp modulators such as CsA without affecting regional distribution in the brain. P-gp modulation could improve the count statistics in PET studies of the CNS. (C) 2000 Wiley-Liss, Inc.

Original languageEnglish
Pages (from-to)66-74
Number of pages9
Issue number1
Publication statusPublished - 16 Mar 2000


  • Blood-brain barrier
  • P-glycoprotein
  • PET
  • β-adrenoceptors

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