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The effect of rifamycin SV and rifampicin on hepatic acid uptake was studied using isolated rat hepatocytes in presence and in absence of albumin. The drugs inhibited cholate uptake more than taurocholate uptake and the inhibition was of non-competitive type. In presence of 3% albumin the inhibitory effect of the drugs was more for cholate and less for taurocholate uptake than in absence of albumin. Neither the binding of bile acids nor that of the drugs to albumin was altered by one another. Thus the effect in presence of albumin cannot be explained by the binding of the drugs and bile acids to albumin alone. It is suggested that albumin interacts with hepatic bile acid uptake process and this interaction with cholate uptake is different from that with taurocholate uptake. This additional and different effect of albumin may explain the effect of the drugs in presence of albumin. The results may be of clinical significance in rifamycins treatments.

Cholic acid uptake was studied in isolated rat hepatocytes using a centrifugal filtration technique to allow rapid sampling. Hepatocytes were found to adsorb as well as to transport cholic acid. The adsorption was characterized by a capacity of 24nmol mg cell protein" 1 and an association constant of 0.59 3 !^" 1 . Cholic acid uptake was linear with respect to concentration at or below 10°C, suggesting a unsaturable uptake process which was considered to represent simple diffusion and is quantitated by a diffusion coefficient of 1.76 pmol cholic acid min" 1 x mg protein" 1 -1 . Above 10 °C the uptake curve was biphasic. After subtracting the unsaturable component from uptake rates at higher tempera-tures, a curve showing saturable kinetics resulted. The apparent K m and V values at 37 °C were calculated to be 61 and 0.8 nmol min" 1 x mg protein" 1 respectively. This saturable uptake process was temperature-dependent with an activation energy of 13 kcal x mol" 1 (5.44 x 10 4 J x mol" 1 ) and was inhibited by oligomycin and KCN. Countertransport was demonstrated with cholic, taurocholic and chenodeoxycholic acids. The results suggest that cholic acid is transported by an energy-dependent carrier-mediated process in addition to simple diffusion by hepatocytes, and that the postulated carrier has affinity for other bile acids.

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The effect of rifamycin SV on hepatic transport of taurocholic acid was investigated using isolated perfused rat liver technique. In all experiments, the perfused liver was maintained at taurocholic acid steady state by infusing constant amount of taurocholic acid. Infusion of rifamycin SV at various rates decreased biliary secretion of bile acids in a dose-dependent manner. Replacement of rifamycin SV by perfusion medium reversed this effect. To determine the site of action of rifamycin SV, kinetic experiments with 14C-taurocholic acid were undertaken. Rifamycin SV elevated the half-life of the medium disappearance of 14C-taurocholic acid. Furthermore, the antibiotic delayed the biliary appearance of 14C-taurocholic acid. The analysis of the results gave indications that the antibiotic interferred with hepatic uptake as well as biliary secretion of taurocholic acid.