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.
Dagenais
C
C
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.
Ducharme
J
J
Pollack
G M
GM
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