Uptake and efflux of the peptidic delta-opioid receptor agonist.
P-glycoprotein (P-gp) and organic anion transporting polypeptides (Oatp) are expressed at the blood-brain barrier (BBB). There is little functional evidence for Oatp-mediated transport at the BBB. The peptidic delta opioid-receptor agonist [D-penicillamine(2,5)]-enkephalin (DPDPE) is a substrate of mdr1a P-gp and Oatp2. The present study evaluated the influence of these transporters on brain uptake of DPDPE by in situ perfusion in mice. Brain uptake was increased approximately 12-fold in mice lacking P-gp in the BBB, but the P-gp inhibitor dexverapamil did not increase uptake in P-gp-competent mice. In P-gp-deficient mice, DPDPE uptake was saturable (K(m) approximately 24 mM), and was inhibited by dexverapamil and the Oatp2 substrates digoxin, estradiol-17beta-glucuronide and fexofenadine. These results confirm P-gp-mediated efflux of DPDPE, and suggest functional uptake transport of DPDPE by Oatp, at the murine BBB.
Division of Drug Delivery and Disposition, School of Pharmacy, Beard Hall CB 7360, The University of North Carolina at Chapel Hill, NC 27599-7360, USA.
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Dagenais
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Ducharme
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Pollack
D018435:ATP Binding Cassette Transporter, Subfamily B / Q000235:genetics*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000701:Analgesics, Opioid / Q000493:pharmacokinetics*; D000818:Animals; D027321:Anion Transport Proteins; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002352:Carrier Proteins / Q000378:metabolism; D004077:Digoxin / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010477:Perfusion; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000378:metabolism*; D016593:Terfenadine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D018435:ATP Binding Cassette Transporter, Subfamily B; D018528:ATP-Binding Cassette Transporters; D000701:Analgesics, Opioid; D027321:Anion Transport Proteins; D002121:Calcium Channel Blockers; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D006634:Histamine H1 Antagonists; D017465:Receptors, Opioid, delta; C025483:estradiol-17 beta-glucuronide; D004958:Estradiol; D004077:Digoxin; D016593:Terfenadine; D020881:Enkephalin, D-Penicillamine (2,5)-; C095122:multidrug resistance protein 3; D014700:Verapamil; C093230:fexofenadine