Transport mechanism of cephalexin in isolated hepatocytes.
By using isolated rat hepatocytes, the mechanism of uptake of a zwitterionic beta-lactam antibiotic, cephalexin, was clarified. The uptake followed the combination of saturable carrier-mediated and nonsaturable first-order rate processes. The kinetic parameters were estimated as follows (mean +/- SD): maximum uptake rate (Vmax), 2.28 +/- 0.24 nmol/min/mg of protein; Michaelis constant (Kt), 6.28 +/- 0.31 mM and first-order rate constant (kd), 0.11 +/- 0.012 nmol/min/mg of protein/mM. There was no inhibitory effect by amino acids, dipeptides or organic cations, whereas an organic anion, probenecid, markedly inhibited the hepatic uptake of cephalexin. Several beta-lactam antibiotics including zwitterionic and anionic derivatives inhibited cephalexin uptake significantly. The inhibition kinetics revealed that benzylpenicillin and the stereo-isomer l-cephalexin competitively inhibited cephalexin uptake. Furthermore, the efflux of cephalexin from the cells was stimulated by adding benzylpenicillin in the extracellular medium. These results demonstrated that all beta-lactam antibiotics have a common transport system with an organic anion such as probenecid, irrespective of their ionic charges, though a cationic charge on the molecule is less advantageous for being recognized by the carrier system.
Tamai
I
I
Faculty of Pharmaceutical Sciences, Kanazawa University Takara-machi, Japan.
Tsuji
A
A
D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D000838:Anions / Q000494:pharmacology; D000900:Anti-Bacterial Agents / Q000378:metabolism; D002412:Cations / Q000494:pharmacology; D002478:Cells, Cultured; D002506:Cephalexin / Q000378:metabolism* / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000494:pharmacology; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D000596:Amino Acids; D000838:Anions; D000900:Anti-Bacterial Agents; D002412:Cations; D004151:Dipeptides; D002506:Cephalexin