Quantitative Evaluation of Blood-Brain Barrier Efflux Transport of Drugs
| Project/Area Number |
07672469
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
応用薬理学・医療系薬学
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| Research Institution | University of Shizuoka |
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Principal Investigator |
DEGUCHI Yoshiharu University of Shizuoka, Department of Biopharmacy, Research Associate, 薬学部, 助手 (40254255)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 1996: ¥300,000 (Direct Cost: ¥300,000)
Fiscal Year 1995: ¥1,300,000 (Direct Cost: ¥1,300,000)
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| Keywords | blood-brain barrier / brain perfusion / efflux transport / microdialysis / monocarboxylic acid transporter / organic anion drugs / probenecid / salicylate / 排出過程 / 脳内薬物動態 / 脳細胞間液 |
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| Research Abstract |
Clarification of the brain distribution of centrally acting pharmaceuticals after systemic administration is important to better understanding their pharmacological effects in the central nervous system. As a rule, the drug concentration in the brain has been known to be regulated by several factors. In particular, the equilibration between blood and brain depends dominantly on the balance of influx and efflux transports across the blood-brain barrier (BBB). However, there are few reports about rate and role of the BBB efflux transport of drugs. Therefore, this study was performed to evaluate quantitatively the influx and efflux transports across the BBB of acidic drugs, using in vivo microdialysis, in situ brain perfusion techniques, intravenous and intra-interstitial-fluid administration method. Probenecid and salicylate were selected as model compounds. The brain interstitial fluid-, cerebrospinal fluid-, and brain tissue-to-plasma unbound concentration ratios of probenecid and sali
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cylate at steady state were less than unity, suggesting restricted distribution in the brain. An uphill concentration gradient from ISF to plasma and a downhill concentration gradient from CSF to ISF,were observed. Kinetic analysis revealed that the efflux clearances of these drugs from brain ISF to plasma were significantly greater than the influx clearances from plasma to brain. The efflux transport of probenecid was significantly inhibited by treatment with N-ethylmaleimide, a sulfhydryl-modifying agent, and salicylate (3.7mM) and benzoate (3.6 mM) which are accepted as substrates of the monocarboxylic acid transport system. On the other hand, p-aminohippuric acid and choline did not produce the inhibition effect. Moreover, the efflux transport of salicylate was inhibited by probenecid (1.4 mM) and benzoate (3.6 mM). These date suggest that the restricted distribution of probenecid and salicylate in the brain may be ascribed to efficient efflux from the brain ISF,which may be regulated by the MCT system at the BBB. Less
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Report
(3 results)
Research Products
(4 results)
