title: Transport of monocarboxylic acids at the blood-brain barrier: studies with monolayers of primary cultured bovine brain capillary endothelial cells.
abstract: 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 +/- 1.87 mM, the maximum uptake rate, Jmax, was 144.7 +/- 55.7 nmol/mg of protein/min and the nonsaturable first-order rate constant, Kd, was 6.66 +/- 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'-diisothiocyanostilben-2,2'-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.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Terasaki
authors.forename: S
authors.initials: S
authors.lastname: Takakuwa
authors.forename: S
authors.initials: S
authors.lastname: Moritani
authors.forename: A
authors.initials: A
authors.lastname: Tsuji
mesh_terms: D019325:3-O-Methylglucose; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000031:analogs & derivatives*; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000085:Acetates / Q000493:pharmacokinetics; D019342:Acetic Acid; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000502:physiology*; D001921:Brain / Q000098:blood supply / Q000166:cytology / Q000378:metabolism; D002196:Capillaries / Q000166:cytology / Q000378:metabolism; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone / Q000494:pharmacology; D002264:Carboxylic Acids / Q000493:pharmacokinetics*; D002417:Cattle; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism*; D006863:Hydrogen-Ion Concentration; D007930:Leucine / Q000493:pharmacokinetics; D008757:Methylglucosides / Q000493:pharmacokinetics; D012459:Salicylates / Q000494:pharmacology; D020156:Salicylic Acid; D014316:Tritium; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D000085:Acetates; D000596:Amino Acids; D002264:Carboxylic Acids; D008757:Methylglucosides; D012459:Salicylates; D014316:Tritium; D019325:3-O-Methylglucose; D012856:4-Acetamido-4'-isothiocyanatostilbene-2,2'-disulfonic Acid; D002259:Carbonyl Cyanide p-Trifluoromethoxyphenylhydrazone; C018564:dihydro-DIDS; D014635:Valproic Acid; D007930:Leucine; D020156:Salicylic Acid; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D019342:Acetic Acid