Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate

Hyperbilirubinemia is a frequent side effect induced by long-term therapy with the antibiotic fusidate. The aim of this study was to elucidate the molecular mechanisms of fusidate-induced hyperbilirubinemia by investigating its influence on hepatic transport systems in the canalicular membrane. Using canalicular membrane vesicles from rat liver, we determined the effect of fusidate on the adenosine 5'-triphosphate (ATP)-dependent transport of substrates of the apical conjugate export pump, multi-drug resistance protein 2 (Mrp2, symbol Abcc2) and the bile salt export pump (Bsep, symbol Abcb11). Fusidate inhibited the ATP-dependent transport of the Mrp2 substrates 17beta-glucuronosyl estradiol and leukotriene C-4, and the transport of cholyltaurine by Bsep with K-i values of 2.2 +/- 0.3, 7.6 +/- 1.3, and 5.5 +/- 0.8 muM, respectively. To elucidate the in vivo implication of these findings, the effect of fusidate treatment on the elimination of intravenously administered tracer doses of 17beta-glucuronosyl estradiol and cholyltaurine into bile was studied in rats. Treatment with fusidate (100 mumol/kg body weight) reduced the biliary excretion rate of 17beta-glucuronosyl [H-3]estradiol and [H-3]cholyltaurine by 75 and 80%, respectively. Extended treatment of rats with fusidate (100 mumol/kg body weight, three times daily i.p. for 3 days) reduced hepatic Mrp2 protein levels by 61% (P < 0.001). Our data suggest that there are at least two different mechanisms involved in the impairment of transport processes and hepatobiliary elimination by fusidate, direct inhibitioin of transport of Mrp2 and Bsep substrates by competitive interaction and impairment by a decreased level of hepatic MrP2. (C) 2002 Elsevier Science Inc. All rights reserved.