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Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences. (PKPD)
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2009 (English)In: Drug Metabolism And Disposition, ISSN 0090-9556, E-ISSN 1521-009X, Vol. 37, no 3, 635-643 p.Article in journal (Refereed) Published
Abstract [en]

Species differences occur in the brain concentrations of drugs, but the reasons for these differences are not yet apparent. This study was designed to compare brain uptake of three radiolabeled P-glycoprotein (P-gp) substrates across species using positron emission tomography. Brain concentrations and brain-to-plasma ratios were compared; [11C]verapamil in rats, guinea pigs, and monkeys; [11C](S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine (GR205171) in rats, guinea pigs, monkeys, and humans; and [18F]altanserin in rats, minipigs, and humans. The fraction of the unbound radioligand in plasma was studied along with its metabolism. The effect of P-gp inhibition was investigated by administering cyclosporin A (CsA). Pronounced species differences were found in the brain and brain-to-plasma concentrations of [11C]verapamil, [11C]GR205171, and [18F]altanserin with higher brain distribution in humans, monkeys, and minipigs than in rats and guinea pigs. For example, the brain-to-plasma ratio of [11C]GR205171 was almost 9-fold higher in humans compared with rats. The species differences were still present after P-gp inhibition, although the increase in brain concentrations after P-gp inhibition was somewhat greater in rats than in the other species. Differences in plasma protein binding and metabolism did not explain the species-related differences. The findings are important for interpretation of brain drug delivery when extrapolating preclinical data to humans. Compounds found to be P-gp substrates in rodents are likely to also be substrates in higher species, but sufficient blood-brain barrier permeability may be retained in humans to allow the compound to act at intracerebral targets.

Place, publisher, year, edition, pages
2009. Vol. 37, no 3, 635-643 p.
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Medical and Health Sciences
URN: urn:nbn:se:uu:diva-103208DOI: 10.1124/dmd.108.024745ISI: 000263516500025PubMedID: 19047468OAI: oai:DiVA.org:uu-103208DiVA: diva2:217760
Available from: 2009-05-15 Created: 2009-05-15 Last updated: 2012-11-22Bibliographically approved

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Syvänen, StinaLångström, BengtHammarlund-Udenaes, Margareta
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Department of Pharmaceutical BiosciencesDepartment of Biochemistry and Organic Chemistry
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Drug Metabolism And Disposition
Medical and Health Sciences

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