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

• Published in: Synapse (New York, N.Y.) N.Y.), 2000-04, Vol.36 (1), p.66-74
• Main Authors: Doze, P., Van Waarde, A., Elsinga, P.H., Hendrikse, N.H., Vaalburg, W.
• Format: Article
• Language: English
• Subjects: Adrenergic beta-Antagonists - pharmacokinetics; Animals; ATP Binding Cassette Transporter, Sub-Family B - drug effects; ATP-Binding Cassette Transporters - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - drug effects; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; b-Adrenergic receptors; blood-brain barrier; 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; P-glycoprotein; PET; Propanolamines - pharmacokinetics; Rats; Rats, Wistar; Tissue Distribution; Tomography, Emission-Computed; β-adrenoceptors
• ISSN: 0887-4476; 1098-2396
• 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 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 (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 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. Synapse 36:66–74, 2000. © 2000 Wiley‐Liss, Inc.