Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier

J Neurochem. 2003 Sep;86(6):1564-7. doi: 10.1046/j.1471-4159.2003.01990.x.


Morphine-6-beta-d-glucuronide (M6G) is an active metabolite of morphine with high analgesic potency despite a low blood-brain barrier (BBB) permeability. The aim of the study was to elucidate its transport mechanism across the BBB. We first checked if M6G was effluxed by the P-glycoprotein (P-gp), as previously reported by others. Second, we investigated the role of anionic transporters like the multidrug resistance-associated protein mrp1 and the glucose transporter GLUT-1. The brain uptake of [14C]M6G was measured by the in situ brain perfusion technique in wild-type and deficient mice [mdr1a(-/-) and mrp1(-/-)], with and without probenecid, digoxin, PSC833 or d-glucose. No difference was found between P-gp and mrp1 competent and deficient mice. The brain uptake of [14C]M6G co-perfused with probenecid in wild-type mice was not significantly different from that found in group perfused with [14C]M6G alone. The co-perfusion of [14C]M6G with digoxin or PSC833 was responsible of a threefold decrease of its uptake in mdr1a competent and deficient mice, suggesting that another transporter than P-gp and sensitive to digoxin and PSC833, may be involved. The co-perfusion of [14C]M6G with d-glucose revealed a threefold decrease in M6G uptake. In conclusion, P-gp and mrp1 are not involved in the transport of M6G at the BBB level in contrast to GLUT-1 and a digoxin-sensitive transporter (probably oatp2), which can actively transport M6G but with a weak capacity.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / deficiency
  • ATP Binding Cassette Transporter, Subfamily B / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • ATP-Binding Cassette Transporters / genetics
  • Animals
  • Biological Transport, Active / drug effects
  • Biological Transport, Active / physiology*
  • Blood-Brain Barrier / drug effects
  • Blood-Brain Barrier / physiology*
  • Brain / metabolism
  • Carbon Radioisotopes
  • Digoxin / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Glucose Transporter Type 1
  • Male
  • Metabolic Clearance Rate
  • Mice
  • Mice, Knockout
  • Monosaccharide Transport Proteins / metabolism
  • Morphine Derivatives / pharmacokinetics*
  • Multidrug Resistance-Associated Proteins / deficiency
  • Multidrug Resistance-Associated Proteins / genetics
  • Perfusion
  • Probenecid / pharmacology
  • Uricosuric Agents / pharmacology


  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP-Binding Cassette Transporters
  • Carbon Radioisotopes
  • Enzyme Inhibitors
  • Glucose Transporter Type 1
  • Monosaccharide Transport Proteins
  • Morphine Derivatives
  • Multidrug Resistance-Associated Proteins
  • Slc2a1 protein, mouse
  • Uricosuric Agents
  • morphine-6-glucuronide
  • Digoxin
  • multidrug resistance protein 3
  • Probenecid
  • multidrug resistance-associated protein 1