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

• Published in: Journal of neurochemistry 2003-09, Vol.86 (6), p.1564-1567
• Main Authors: Bourasset, Fanchon, Cisternino, Salvatore, Temsamani, Jamal, Scherrmann, Jean‐Michel
• Format: Article
• Language: English
• Subjects: Animals; 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; Biological and medical sciences; Biological Transport, Active - drug effects; Biological Transport, Active - physiology; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - physiology; blood–brain barrier; Brain - metabolism; Carbon Radioisotopes; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Digoxin - pharmacology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Glucose Transporter Type 1; GLUT‐1; Male; Metabolic Clearance Rate; Mice; Mice, Knockout; Monosaccharide Transport Proteins - metabolism; Morphine Derivatives - pharmacokinetics; morphine‐6‐β‐d‐glucuronide; mrp1; Multidrug Resistance-Associated Proteins - deficiency; Multidrug Resistance-Associated Proteins - genetics; Perfusion; Probenecid - pharmacology; P‐glycoprotein; Uricosuric Agents - pharmacology; Vertebrates: nervous system and sense organs
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1046/j.1471-4159.2003.01990.x

Morphine‐6‐β‐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.