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

Synapse. 2000 Apr;36(1):66-74. doi: 10.1002/(SICI)1098-2396(200004)36:1<66::AID-SYN7>3.0.CO;2-J.


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 beta-adrenergic ligands S-1'-[(18)F]-fluorocarazolol (FCAR) and [(11)C]-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 (AUC)) 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 AUC. 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 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / drug effects
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / drug effects*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP-Binding Cassette Transporters / drug effects
  • Adrenergic beta-Antagonists / pharmacokinetics
  • Animals
  • Blood-Brain Barrier / drug effects*
  • Blood-Brain Barrier / genetics
  • Brain / diagnostic imaging
  • Brain / drug effects
  • Brain / metabolism*
  • Carbazoles / pharmacokinetics
  • Cyclosporine / pharmacology
  • Fluorine Radioisotopes
  • Immunohistochemistry
  • Ligands
  • Male
  • Mice
  • Mice, Knockout
  • Propanolamines / pharmacokinetics
  • Rats
  • Rats, Wistar
  • Tissue Distribution
  • Tomography, Emission-Computed


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Adrenergic beta-Antagonists
  • Carbazoles
  • Fluorine Radioisotopes
  • Ligands
  • Propanolamines
  • fluorocarazolol
  • carazolol
  • Cyclosporine
  • multidrug resistance protein 3