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Involvement of an influx transporter in the blood–brain barrier transport of naloxone
Author(s) -
Suzuki Toyofumi,
Ohmuro Aya,
Miyata Mariko,
Furuishi Takayuki,
Hidaka Shinji,
Kugawa Fumihiko,
Fukami Toshiro,
Tomono Kazuo
Publication year - 2010
Publication title -
biopharmaceutics and drug disposition
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.419
H-Index - 58
eISSN - 1099-081X
pISSN - 0142-2782
DOI - 10.1002/bdd.707
Subject(s) - chemistry , (+) naloxone , tetraethylammonium , blood–brain barrier , organic cation transport proteins , organic anion , pharmacology , lipophilicity , antagonist , in vivo , transporter , endocrinology , biochemistry , receptor , central nervous system , ion , medicine , microbiology and biotechnology , potassium , organic chemistry , biology , gene
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 µ M to 15 m M ) 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 m M ; the maximum uptake rate, J max , was 0.477±0.083 µmol/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. Copyright © 2010 John Wiley & Sons, Ltd.