title: Brain penetration of synthetic adenosine A1 receptor agonists in situ: role of the rENT1 nucleoside transporter and binding to blood constituents.
abstract: The blood-brain barrier (BBB) transport of synthetic A(1) receptor agonists was studied in an in situ brain perfusion model in the presence and absence of the selective nucleoside transport inhibitor S-(4-nitrobenzyl)-6-thioinosine (NBTI). For 8-methylamino-N(6)cyclopentyladenosine (MCPA), N(6)-cyclopentyladenosine (CPA), 2'deoxy-N(6)-cyclopentyladenosine (2'dCPA) and 5'deoxy-N(6)-cyclopentyl adenosine (5'dCPA) the brain uptake clearance was low with values of 0.0045+/-0.0012, 0.018+/-0.0020, 0.022+/-0.0028 and 0.12+/-0.054 ml min(-1)g(-1), respectively. In the presence of an average NBTI plasma concentration of 2.6+/-0.3 microg ml(-1) (NBTI dose: 3 mg kg(-1) i.v.) the values of the brain uptake clearance were 0.0062+/-0.0012, 0.013+/-0.0017, 0.014+/-0.0030 and 0.13+/-0.066 ml min(-1)g(-1), respectively and not significantly different from the values in the absence of NBTI. In a separate experiment the brain uptake of MCPA from phosphate buffered saline (PBS) and whole blood were compared. The brain uptake clearance from whole blood (0.0012+/-0.001 ml min(-1)g(-1)) was significantly lower than from PBS (0.0045+/-0.0012 ml min(-1)g(-1)). The results of these studies show that the rENT1 nucleoside transporter does not contribute significantly to the transport of synthetic A(1) receptor agonists across the BBB and that binding to blood constituents restricts the brain uptake.
authors.affiliation: Division of Pharmacology, Leiden/Amsterdam Center for Drug Research, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
authors.forename: Marloes P
authors.initials: MP
authors.lastname: Schaddelee
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.forename: Cindy G J
authors.initials: CG
authors.lastname: Cleypool
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
authors.forename: Meindert
authors.initials: M
authors.lastname: Danhof
authors.forename: Albertus G
authors.initials: AG
authors.lastname: de Boer
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics; D058907:Adenosine A1 Receptor Agonists; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D033721:Equilibrative Nucleoside Transporter 1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D010539:Permeability / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D043682:Receptor, Adenosine A1 / Q000378:metabolism; D013868:Thioinosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C495035:8-methylamino-N6-cyclopentyladenosine; D058907:Adenosine A1 Receptor Agonists; D033721:Equilibrative Nucleoside Transporter 1; D043682:Receptor, Adenosine A1; C438652:Slc29a1 protein, rat; D013868:Thioinosine; C001789:4-nitrobenzylthioinosine; D000241:Adenosine