Uptake and efflux of the peptidic delta-opioid receptor agonist

Neurosci Lett. 2001 Apr 6;301(3):155-8. doi: 10.1016/s0304-3940(01)01640-8.

Abstract

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / genetics*
  • ATP-Binding Cassette Transporters / genetics*
  • Analgesics, Opioid / pharmacokinetics*
  • Animals
  • Anion Transport Proteins
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / physiology*
  • Calcium Channel Blockers / pharmacology
  • Carrier Proteins / metabolism
  • Digoxin / pharmacology
  • Enkephalin, D-Penicillamine (2,5)- / pharmacokinetics*
  • Enzyme Inhibitors / pharmacology
  • Estradiol / analogs & derivatives
  • Estradiol / pharmacology
  • Histamine H1 Antagonists / pharmacology
  • Male
  • Mice
  • Mice, Knockout
  • Perfusion
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / metabolism*
  • Terfenadine / analogs & derivatives*
  • Terfenadine / pharmacology
  • Verapamil / pharmacology

Substances

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP-Binding Cassette Transporters
  • Analgesics, Opioid
  • Anion Transport Proteins
  • Calcium Channel Blockers
  • Carrier Proteins
  • Enzyme Inhibitors
  • Histamine H1 Antagonists
  • Receptors, Opioid, delta
  • estradiol-17 beta-glucuronide
  • Estradiol
  • Digoxin
  • Terfenadine
  • Enkephalin, D-Penicillamine (2,5)-
  • multidrug resistance protein 3
  • Verapamil
  • fexofenadine