Inhibition of hepatic uptake of bile acids by rifamycins

Abstract

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.

Rifamycin SV and rifampicin exhibit differential inhibition of the hepatic rat organic anion transporting polypeptides, Oatp1 and Oatp2

“…Our results regarding total taurocholate uptake are consistent with the previously reported K i estimates of 60 µmol/L for rifamycin SV and 122 µmol/L for rifampicin. 8 Because under these experimental conditions sodium-dependent uptake accounted for 90% of total taurocholate uptake (see above), the previously reported K i estimates mainly characterized sodium-dependent taurocholate uptake. It has been suggested that based on antisense experiments in liver cRNA-injected oocytes that Ntcp represents the main sodium-dependent taurocholate uptake system of rat liver.…”

“…Because the inhibitory effects of rifamycin SV and rifampicin on hepatocellular bile salt uptake were previously only studied in the presence of sodium, 8 we first investigated the separate effects of rifamycin SV and rifampicin on both sodium-dependent and sodium-independent taurocholate uptake in short-term-cultured hepatocytes. Both inhibitors were added at concentrations of 10 µmol/L and 100 µmol/L.…”

“…8,24 In the present study, we have further characterized the different uptake systems involved. Our results regarding total taurocholate uptake are consistent with the previously reported K i estimates of 60 µmol/L for rifamycin SV and 122 µmol/L for rifampicin.…”

“…8 The corresponding K i values for taurocholate were 60 and 122 µmol/L in the absence and 128 and 237 µmol/L in the presence of bovine serum albumin. 8 The values reported for cholate are close to the serum concentrations of 5 to 10 µmol/L measured after administration of therapeutic doses of rifamycin SV or rifampicin in humans. 1,9 Recently, several carrier proteins involved in the hepatic uptake of bile salts and other albumin-bound organic anions have been cloned from rat liver.…”

“…7 In isolated rat hepatocytes, rifamycin SV and rifampicin inhibited cholate uptake, with K i values of 30 and 46 µmol/L in the absence and of 18 and 31 µmol/L in the presence of bovine serum albumin (3%). 8 The corresponding K i values for taurocholate were 60 and 122 µmol/L in the absence and 128 and 237 µmol/L in the presence of bovine serum albumin. 8 The values reported for cholate are close to the serum concentrations of 5 to 10 µmol/L measured after administration of therapeutic doses of rifamycin SV or rifampicin in humans.…”