title: Blood-brain barrier transport of naloxone does not involve P-glycoprotein-mediated efflux.
abstract: The blood-brain barrier (BBB) transport of naloxone, a potent and specific opioid antagonist, was investigated in rats using the brain uptake index method and the brain efflux index method. The apparent influx clearance of [(3)H]naloxone across the BBB was 0.305 mL/min/g brain. [(3)H]naloxone was eliminated from the brain with an apparent elimination half-life of 15.1 min after microinjection into the parietal cortex area 2 regions of the rat brain. The apparent efflux clearance of [(3)H]naloxone across the BBB was 0.152 mL/min/g brain, which was calculated from the elimination rate constant (4.79 x 10(-2) min(-1)) and the distribution volume in the brain (3.18 mL/g brain). The influx clearance across the BBB was two times greater than the efflux clearance. The elimination of [(3)H]naloxone from the brain was not inhibited in the presence of the typical P-glycoprotein (P-gp) inhibitors such as quinidine, verapamil, vinblastine, and vincristine, indicating that naloxone is not a P-gp substrate in the rat. In vitro experiments by using human multidrug resistance 1 (MDR1)/P-gp overexpressing HeLa cells showed that the uptake of naloxone by the cells did not change in the presence of the P-gp inhibitors. In conclusion, the present results obtained from in vivo and in vitro studies suggest that P-gp is not involved in the BBB transport of naloxone.
authors.affiliation: Department of Pharmaceutics, College of Pharmacy, Nihon University, Chiba, Japan. suzuki.toyofumi@nihon-u.ac.jp
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Mariko
authors.initials: M
authors.lastname: Miyata
authors.forename: Chika
authors.initials: C
authors.lastname: Zaima
authors.forename: Takayuki
authors.initials: T
authors.lastname: Furuishi
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fukami
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kugawa
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tomono
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism* / Q000502:physiology; D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006367:HeLa Cells; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008845:Microinjections; D008954:Models, Biological; D009270:Naloxone / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar; D014018:Tissue Distribution
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D009292:Narcotic Antagonists; D009270:Naloxone