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-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.
Doze
P
P
PET-center, Groningen University Hospital, Groningen, The Netherlands. P.Doze@pet.azg.nl
Van Waarde
A
A
Elsinga
P H
PH
Hendrikse
N H
NH
Vaalburg
W
W
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects* / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000235:genetics; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002227:Carbazoles / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000494:pharmacology; D005462:Fluorine Radioisotopes; D007150:Immunohistochemistry; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011412:Propanolamines / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D005462:Fluorine Radioisotopes; D008024:Ligands; D011412:Propanolamines; C089702:fluorocarazolol; C014382:carazolol; D016572:Cyclosporine; C095122:multidrug resistance protein 3