title: Role of blood-brain barrier P-glycoprotein in limiting brain accumulation and sedative side-effects of asimadoline, a peripherally acting analgaesic drug.
abstract: Studies with knockout mice lacking mdr1a P-glycoprotein (P-gp) have previously shown that blood-brain barrier P-gp is important in preventing the accumulation of several drugs in the brain. Asimadoline (EMD 61753) is a peripherally selective kappa-opioid receptor agonist which is under development as a therapeutic analgaesic. From the structural characteristics of this drug and its peripheral selectivity, we hypothesized that it is transported by P-gp. Using a pig-kidney polarized epithelial cell line transfected with mdr cDNAs, we demonstrate that asimadoline is transported by the mouse mdr1a P-gp and the human MDR1 P-gp. Furthermore, we show that in mdr1a/1b double knockout mice, the absence of P-gp leads to a 9 fold increased accumulation of asimadoline in the brain. In line with this accumulation difference, mdr1a/1b (-/-) mice are at least 8 fold more sensitive to the sedative effect of asimadoline than wild-type mice. Interestingly, the oral uptake of asimadoline was not substantially altered in mdr1a/1b (-/-) mice. Our results demonstrate that for some drugs, P-gp in the blood-brain barrier can have a therapeutically beneficial effect by limiting brain penetration, whereas at the same time intestinal P-gp is not a significant impediment to oral uptake of the drug.
authors.affiliation: The Netherlands Cancer Institute, Division of Experimental Therapy, Amsterdam.
authors.forename: J W
authors.initials: JW
authors.lastname: Jonker
authors.forename: E
authors.initials: E
authors.lastname: Wagenaar
authors.forename: L
authors.initials: L
authors.lastname: van Deemter
authors.forename: R
authors.initials: R
authors.lastname: Gottschlich
authors.forename: H M
authors.initials: HM
authors.lastname: Bender
authors.forename: J
authors.initials: J
authors.lastname: Dasenbrock
authors.forename: A H
authors.initials: AH
authors.lastname: Schinkel
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000081:Acetamides / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D000701:Analgesics, Opioid / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D000818:Animals; D001682:Biological Availability; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011759:Pyrrolidines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D012894:Sleep Stages / Q000187:drug effects*; D013552:Swine; D014018:Tissue Distribution; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000081:Acetamides; D000701:Analgesics, Opioid; D011759:Pyrrolidines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C095122:multidrug resistance protein 3; C092095:asimadoline