Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 99, Issue 1, Pages 413-421Publisher
JOHN WILEY & SONS INC
DOI: 10.1002/jps.21819
Keywords
naloxone; blood-brain barrier; P-glycoprotein; transport
Funding
- High-Tech Research Center
- Academic Frontier
- MEXT (Ministry of Education, Culture, Sports, Science and Technology) in Japan
- Nihon University General Individual Research [07-111]
- A Joint Research Grant from Nihon University College of Pharmacy
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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. (C) 2009 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 99:413-421, 2010
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