title: Blood-brain barrier transport of pramipexole, a dopamine D2 agonist.
abstract: The blood-brain barrier (BBB) transport of pramipexole, a potent dopamine receptor agonist with high efficacy for Parkinson's disease, was mainly characterized using immortalized rat brain capillary endothelial cells (RBEC)1 as an in vitro BBB model. [(14)C]Pramipexole uptake by RBEC1 was dependent on temperature and pH, but not sodium ion concentration or membrane potential. The uptake was inhibited by several organic cations including pyrilamine. Mutual inhibition was observed between pramipexole and pyrilamine. In addition, [(14)C]pramipexole uptake was stimulated by preloading unlabeled pramipexole. RT-PCR analysis for organic cation transporters (rOCT1-3, rOCTN1-2) in RBEC1 was performed. The mRNA level of rOCTN2 was the highest, followed by rOCTN1, while expression of rOCT1, rOCT2 and rOCT3 was negligible. The brain uptake of [(14)C]pramipexole, which was measured by the in situ rat brain perfusion technique, was significantly inhibited by unlabeled pramipexole. These results suggest that pramipexole is, at least in part, transported across the BBB by an organic cation-sensitive transporter. The pramipexole transport in RBEC1 was pH-dependent, but sodium- and membrane potential-independent.
authors.affiliation: Department of Drug Disposition & Pharmacokinetics, School of Pharmaceutical Sciences, Teikyo University, 1091-1 Suarashi, Sagamiko, Sagamihara, Kanagawa 199-0195, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Okura
authors.forename: Rie
authors.initials: R
authors.lastname: Ito
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.forename: Ikumi
authors.initials: I
authors.lastname: Tamai
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Deguchi
mesh_terms: D000818:Animals; D052160:Benzothiazoles / Q000378:metabolism* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002250:Carbon Radioisotopes / Q000378:metabolism; D002412:Cations / Q000494:pharmacology; D002461:Cell Line, Transformed; D054815:Cyclic Nucleotide-Gated Cation Channels; D018491:Dopamine Agonists / Q000378:metabolism* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004730:Endothelium, Vascular / Q000378:metabolism; D015870:Gene Expression; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D010477:Perfusion; D000077487:Pramipexole; D011738:Pyrilamine / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017448:Receptors, Dopamine D2 / Q000819:agonists*
chemical_list: D052160:Benzothiazoles; D002250:Carbon Radioisotopes; D002412:Cations; C518239:Cnga2 protein, rat; D054815:Cyclic Nucleotide-Gated Cation Channels; D018491:Dopamine Agonists; D007473:Ion Channels; D029362:Organic Anion Transporters, Sodium-Independent; D012333:RNA, Messenger; D017448:Receptors, Dopamine D2; C114338:organic anion transport protein 3; D000077487:Pramipexole; D011738:Pyrilamine