Defining the inhibitory potential of uremic toxins on erythromycin hepatic metabolism

Abstract

Hepatic clearance of erythromycin is significantly reduced in end stage renal disease (ESRD) patients. To determine whether uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF) and indoxyl sulfate can directly inhibit the liver uptake of erythromycin, rat hepatocytes were incubated with erythromycin in the presence of these toxins. Intracellular concentrations of erythromycin and its demethylated metabolite were measured by LC/MS/MS. CMPF at concentrations normally present in ESRD patients (200μM) significantly inhibited the intracellular accumulation of erythromycin and correspondingly its metabolite (68.2±2.4%, 71.8±4.9%, respectively, p<0.05). The inhibitory effect was dose-dependent. CMPF showed little effect on the enzymatic metabolism of erythromycin. In contrast, indoxyl sulfate did not significantly inhibit the uptake of erythromycin even at concentrations of 1000μM, but showed more pronounced inhibition of metabolite generation (59.1±3.6%, p<0.05). When incubated with microsomes, indoxyl sulfate (100μM) significantly inhibited the metabolism of erythromycin (26% reduction, p<0.05). These data suggest that CMPF can directly inhibit the uptake of erythromycin by hepatocytes, most likely by inhibiting uptake transporters, while indoxyl sulfate is more likely to inhibit the enzymatic metabolism of erythromycin. The inhibitory effects of these uremic toxins may directly contribute to the reduced hepatic clearance of erythromycin in ESRD patients. Clinical Pharmacology & Therapeutics (2004) 75, P62–P62; doi: 10.1016/j.clpt.2003.11.235