title: Species differences in blood-brain barrier transport of three positron emission tomography radioligands with emphasis on P-glycoprotein transport.
abstract: 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; [(11)C]verapamil in rats, guinea pigs, and monkeys; [(11)C](S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine (GR205171) in rats, guinea pigs, monkeys, and humans; and [(18)F]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 [(11)C]verapamil, [(11)C]GR205171, and [(18)F]altanserin with higher brain distribution in humans, monkeys, and minipigs than in rats and guinea pigs. For example, the brain-to-plasma ratio of [(11)C]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.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. s.syvanen@lacdr.leidenuniv.nl
authors.forename: Stina
authors.initials: S
authors.lastname: Syvänen
authors.forename: Orjan
authors.initials: O
authors.lastname: Lindhe
authors.forename: Mikael
authors.initials: M
authors.lastname: Palner
authors.forename: Birgitte R
authors.initials: BR
authors.lastname: Kornum
authors.forename: Obaidur
authors.initials: O
authors.lastname: Rahman
authors.forename: Bengt
authors.initials: B
authors.lastname: Långström
authors.forename: Gitte M
authors.initials: GM
authors.lastname: Knudsen
authors.forename: Margareta
authors.initials: M
authors.lastname: Hammarlund-Udenaes
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D001812:Blood-Brain Barrier; D006168:Guinea Pigs; D006801:Humans; D008252:Macaca fascicularis; D049268:Positron-Emission Tomography; D011485:Protein Binding; D021381:Protein Transport; D011869:Radioligand Assay; D051381:Rats; D013045:Species Specificity
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001798:Blood Proteins