title: Evidence for an active transport of morphine-6-beta-d-glucuronide but not P-glycoprotein-mediated at the blood-brain barrier.
abstract: 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.
authors.affiliation: INSERM U26, Hôpital Fernand Widal, Paris, France. Fanchon.Bourasset@fwidal.inserm.fr
authors.forename: Fanchon
authors.initials: F
authors.lastname: Bourasset
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cisternino
authors.forename: Jamal
authors.initials: J
authors.lastname: Temsamani
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Scherrmann
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects / Q000502:physiology*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000502:physiology*; D001921:Brain / Q000378:metabolism; D002250:Carbon Radioisotopes; D004077:Digoxin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051272:Glucose Transporter Type 1; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009022:Morphine Derivatives / Q000493:pharmacokinetics*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000172:deficiency / Q000235:genetics; D010477:Perfusion; D011339:Probenecid / Q000494:pharmacology; D014528:Uricosuric Agents / Q000494:pharmacology
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D002250:Carbon Radioisotopes; D004077:Digoxin; D004791:Enzyme Inhibitors; D051272:Glucose Transporter Type 1; D009004:Monosaccharide Transport Proteins; D009022:Morphine Derivatives; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D011339:Probenecid; D014528:Uricosuric Agents; C495678:Slc2a1 protein, mouse; C035349:morphine-6-glucuronide; C095122:multidrug resistance protein 3; C421109:multidrug resistance-associated protein 1