title: Involvement of an influx transporter in the blood-brain barrier transport of naloxone.
abstract: Naloxone, a potent and specific opioid antagonist, has been shown in previous studies to have an influx clearance across the rat blood-brain barrier (BBB) two times greater than the efflux clearance. The purpose of the present study was to characterize the influx transport of naloxone across the rat BBB using the brain uptake index (BUI) method. The initial uptake rate of [(3)H]naloxone exhibited saturability in a concentration-dependent manner (concentration range 0.5 microM to 15 mM) in the presence of unlabeled naloxone. These results indicate that both passive diffusion and a carrier-mediated transport mechanism are operating. The in vivo kinetic parameters were estimated as follows: the Michaelis constant, K(t), was 2.99+/-0.71 mM; the maximum uptake rate, J(max), was 0.477+/-0.083 micromol/min/g brain; and the nonsaturable first-order rate constant, K(d), was 0.160+/-0.044 ml/min/g brain. The uptake of [(3)H]naloxone by the rat brain increased as the pH of the injected solution was increased from 5.5 to 8.5 and was strongly inhibited by cationic H(1)-antagonists such as pyrilamine and diphenhydramine and cationic drugs such as lidocaine and propranolol. In contrast, the BBB transport of [(3)H]naloxone was not affected by any typical substrates for organic cation transport systems such as tetraethylammonium, ergothioneine or L-carnitine or substrates for organic anion transport systems such as p-aminohippuric acid, benzylpenicillin or pravastatin. The present results suggest that a pH-dependent and saturable influx transport system that is a selective transporter for cationic H(1)-antagonists is involved in the BBB transport of naloxone in the rat.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Nihon University, 7-7-1 Narashinodai, Funabashi, Chiba, Japan.
authors.forename: Toyofumi
authors.initials: T
authors.lastname: Suzuki
authors.forename: Aya
authors.initials: A
authors.lastname: Ohmuro
authors.forename: Mariko
authors.initials: M
authors.lastname: Miyata
authors.forename: Takayuki
authors.initials: T
authors.lastname: Furuishi
authors.forename: Shinji
authors.initials: S
authors.lastname: Hidaka
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Kugawa
authors.forename: Toshiro
authors.initials: T
authors.lastname: Fukami
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tomono
mesh_terms: D000818:Animals; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D002412:Cations; D004058:Diffusion; D004305:Dose-Response Relationship, Drug; D005260:Female; D006863:Hydrogen-Ion Concentration; D009270:Naloxone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D009292:Narcotic Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002412:Cations; D009292:Narcotic Antagonists; D009270:Naloxone