PT  - JOURNAL ARTICLE
AU  - Stina Syvänen
AU  - Örjan Lindhe
AU  - Mikael Palner
AU  - Birgitte R. Kornum
AU  - Obaidur Rahman
AU  - Bengt Långström
AU  - Gitte M. Knudsen
AU  - Margareta Hammarlund-Udenaes
TI  - Species Differences in Blood-Brain Barrier Transport of Three Positron Emission Tomography Radioligands with Emphasis on P-Glycoprotein Transport
AID  - 10.1124/dmd.108.024745
DP  - 2009 Mar 01
TA  - Drug Metabolism and Disposition
PG  - 635--643
VI  - 37
IP  - 3
4099  - http://dmd.aspetjournals.org/content/37/3/635.short
4100  - http://dmd.aspetjournals.org/content/37/3/635.full
SO  - Drug Metab Dispos2009 Mar 01; 37
AB  - 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. The American Society for Pharmacology and Experimental Therapeutics