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I Tamai, T Maekawa and A Tsuji
Faculty of Pharmaceutical Sciences, Kanazawa University, Japan.
The biliary excretion mechanism of cefpiramide, a typical biliary excretion type cephalosporin antibiotic, was investigated by measuring the uptake by purified rat liver bile canalicular membrane vesicles. The initial uptake of cefpiramide showed significant temperature and concentration dependencies; the kinetic parameters were estimated to be 1.73 mM, 2.64 nmol/40 sec/mg protein and 0.17 nmol/40 sec/mg protein/mM for Michaelis constant, maximum uptake rate and nonsaturable uptake rate constant, respectively. An intravesicular positive membrane potential induced by valinomycin significantly enhanced the initial uptake of cefpiramide. Furthermore, by inducing an inside negative membrane potential, the initial efflux was significantly enhanced. Organic anions such as bile acids, bromosulfophthalein, bilirubin, probenecid, furosemide and 4,4'-diisothiocyanostilben-2,2'-disulfonic acid significantly reduced the uptake of cefpiramide, whereas amino acids, dipeptides, organic neutral compounds and cationic compounds had no effect. The inhibitory effects of taurocholic acid and bromosulfopthalein were especially competitive. Most of the beta-lactam antibiotics tested significantly reduced the uptake of cefpiramide in a competitive manner. Furthermore, benzylpenicillin showed a countertransport effect on the cefpiramide uptake. From these results it is suggested that neither organic cation nor dipeptide carrier systems participate in the uptake of beta-lactam antibiotics, and most of the derivatives are transported by recognition as organic anions in the bile canalicular membrane.
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