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

Abstract

The antibiotics, rifamycin SV and rifampicin, are known to interfere with hepatic bile salt and organic anion uptake. The aim of this study was to explore which transport systems are affected. In short-term-cultured rat hepatocytes, low concentrations (10 mol/L) of both compounds inhibited mainly sodium-independent taurocholate uptake, whereas higher concentrations (100 mol/L) also inhibited sodium-dependent taurocholate uptake. In Xenopus laevis oocytes expressing the Na ؉ /taurocholate cotransporting polypeptide (Ntcp), high rifamycin SV and rifampicin concentrations were required for inhibition of taurocholate uptake. In contrast, sodiumindependent taurocholate uptake mediated by the organic anion transporting polypeptides, Oatp1 and Oatp2, was already substantially inhibited by 10 mol/L rifamycin SV. Rifampicin potently inhibited Oatp2-mediated taurocholate uptake, but did not interfere with Oatp1-mediated taurocholate uptake. Similar effects of rifamycin SV and rifampicin were found for Oatp1-and Oatp2-mediated estradiol-17␤-glucuronide transport. Dixon plot analysis yielded a pattern compatible with competitive inhibition of estradiol-17␤-glucuronide transport with K i estimates of 6.6 mol/L and 7.3 mol/L for rifamycin SV-induced inhibition of Oatp1 and Oatp2, respectively, and of 1.4 mol/L for rifampicin-induced inhibition of Oatp2. These results demonstrate that rifamycin SV and rifampicin exhibit differential inhibition on Oatp1 and Oatp2, and identify rifampicin as a selective Oatp2 inhibitor. The data indicate that these inhibitors can be used to determine the in vivo relevance of Oatp1 and Oatp2 for the overall bioavailability and disposition of drugs and other Oatp1/2 substrates. (HEPATOLOGY 2000;32:82-86.)The antibiotics, rifamycin SV and rifampicin, are mainly eliminated by hepatic uptake, metabolism, and excretion into bile. 1,2 For rifamycin SV, hepatic first-pass elimination is so efficient that oral administration is unfeasible. 3 Rifamycin SV interferes with the hepatic elimination of many compounds including bilirubin, bromosulfophtalein, and indocyanine green. 4,5 Rifampicin has been shown to increase serum bile salt concentrations in 72% of patients 6 after the first dose, suggesting acute inhibition of hepatocellular bile salt uptake. 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. 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. 10 The Na ϩ /taurocholate cotransporting polypeptide, Ntcp, mediates sodiu...

Quantitative intravital microscopy of hepatic transport

“…This result is consistent with previous studies in which rifampin has been found to inhibit hepatic uptake in cultured rat hepatocytes 51 and perfused rat liver. 53 However, our results are novel in that they, (1) demonstrate that rifampin blocks uptake by hepatocytes in the intact liver in vivo, (2) demonstrate that rifampin blocks the initial step of uptake into the cytosol and (3) demonstrate that inhibition delivery of bilirubin to the hepatocyte cytosol, where conjugation occurs, this is a surprising result.…”

“…In order to demonstrate the sensitivity of the liver transport assays, we evaluated transport in rats treated for 4 d with rifampin, an antibiotic used to treat tuberculosis, and a potent inhibitor of rat and human organic anion transporters. [50][51][52][53][54] The time course of fluorescein redistribution over 6 min in rifampintreated and vehicle-treated control rats is shown in Figure 3. The top three panels show that, similar to the results shown in Figure 2, fluorescein rapidly redistributes from the sinusoids into the hepatocyte cytosol and canaliculi in a control rat.…”

Organic anion transporting polypeptide 1a/1b–knockout mice provide insights into hepatic handling of bilirubin, bile acids, and drugs

“…Previous in vitro studies have shown that rifampicin is an inhibitor of Oatp1a4, Oatp1b2, OATP1B1, and OATP1B3 (44)(45)(46). Rifampicin, an antibiotic mainly used in the treatment of tuberculosis, has been shown to reduce the elimination of BSP and to increase serum-conjugated bilirubin and UCB levels (30,47).…”

The emerging role of transport systems in liver function tests

“…For example, uptake of ICG is inhibited by rifamycin (Paumgartner, 1975), which is a potent liver OATP inhibitor (Fattinger et al, 2000;Vavricka et al, 2002). In contrast, coadministration of erythromycin and gadoxetic acid was recently found to have no effect on liver imaging (Huppertz et al, 2011).…”