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; [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.
Footnotes
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This work was supported by GE Healthcare and EC-FP6-project DiMI [Grant LSHB-CT-2005-512146].
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.108.024745.
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ABBREVIATIONS: P-gp, P-glycoprotein; MDR, multidrug resistance; PET, positron emission tomography; 5HT, 5-hydroxytryptamine (serotonin); RWAY, 2,3,4,5, 6,7-hexahydro-1{4-[1[4-(2-methoxyphenyl)-piperazinyl]]-2-phenylbutyry}-1H-azepine; [18F]MPPF, 4-(2′-methoxyphenyl)-1-[2′-(N-2″-pyridinyl)-p-[18F]fluorobenzamido]ethylpiperazine; GR205171, 2 (S)-(2-methoxy-5-(5-trifluoromethyltetrazol-1-yl)-phenylmethylamino)-2(S)-phenylpiperidine; NK, neurokinin; GF-120918, N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-isoquinolinyl)ethyl]-phenyl)-9,10-dihydro-5-methoxy-9-oxo-4-acridine carboxamide; CsA, cyclosporin A; ROI, region of interest; fp, plasma protein unbound fraction; Kp, brain-to-plasma concentration ratio; Kp,increase, increase in Kp after cyclosporin A administration; Rbuffer, radioactivity concentration in buffer; Rplasma, radioactivity concentration in plasma; SUV, standardized uptake value; SUVincrease, increase in standardized uptake value after cyclosporin A administration; PSC833, valspodar.
- Received October 7, 2008.
- Accepted November 24, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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