Transport of monocarboxylic acids at the blood-brain barrier: Studies with monolayers of primary cultured bovine brain capillary endothelial cells
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University (Japan)
The kinetics and mechanism of the transport of monocarboxylic acids (MCAs) were studied by using primary cultured bovine brain capillary endothelial cells. Concentration-dependent uptake of acetic acid was observed, and the kinetic parameters were estimated as follows: the Michaelis constant, Kt, was 3.41 {plus minus} 1.87 mM, the maximum uptake rate, Jmax, was 144.7 {plus minus} 55.7 nmol/mg of protein/min and the nonsaturable first-order rate constant, Kd, was 6.66 {plus minus} 1.98 microliters/mg of protein/min. At medium pH below 7.0, the uptake rate of (3H)acetic acid increased markedly with decreasing medium pH, whereas pH-independent uptake was observed in the presence of 10 mM acetic acid. An energy requirement for (3H)acetic acid uptake was also demonstrated, because metabolic inhibitors (2,4-dinitrophenol and rotenone) reduced significantly the uptake rate (P less than .05). Carbonylcyanide-p-trifluoro-methoxyphenylhydrazone, a protonophore, inhibited significantly the uptake of (3H)acetic acid at medium pH of 5.0 and 6.0, whereas 4,4{prime}-diisothiocyanostilben-2,2{prime}-disulfonic acid did not. Several MCAs inhibited significantly the uptake rate of (3H)acetic acid, whereas di- and tricarboxylic acids did not. The uptake of (3H)acetic acid was competitively inhibited by salicylic acid, with an inhibition constant, Ki, of 3.60 mM, suggesting a common transport system between acetic acid and salicylic acid. Moreover, at the medium pH of 7.4, salicylic acid and valproic acid inhibited significantly the uptake of (3H)acetic acid, demonstrating that the transport of MCA drugs could also be ascribed to the MCA transport system at the physiologic pH.
- OSTI ID:
- 5031456
- Journal Information:
- Journal of Pharmacology and Experimental Therapeutics; (United States), Vol. 258:3; ISSN 0022-3565
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
CARBOXYLIC ACIDS
MEMBRANE TRANSPORT
AMINO ACIDS
BLOOD-BRAIN BARRIER
BRAIN
CAPILLARIES
CATTLE
DOSE-RESPONSE RELATIONSHIPS
ENDOTHELIUM
ENZYME INHIBITORS
LEUCINE
PH VALUE
TRITIUM COMPOUNDS
ANIMAL TISSUES
ANIMALS
BLOOD VESSELS
BODY
CARDIOVASCULAR SYSTEM
CENTRAL NERVOUS SYSTEM
DOMESTIC ANIMALS
HYDROGEN COMPOUNDS
MAMMALS
NERVOUS SYSTEM
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
RUMINANTS
TISSUES
VERTEBRATES
550201* - Biochemistry- Tracer Techniques