Received for publication May 10, 2004.
Revised July 29, 2004.
Accepted for publication July 30, 2004.

EFFECTS OF UREMIC TOXINS ON HEPATIC UPTAKE AND METABOLISM OF ERYTHROMYCIN

Abstract

Hepatic clearance of erythromycin (Ery) is significantly reduced in patients with end stage renal disease (ESRD). Since Ery is primarily eliminated via excretion of unchanged drug in the bile, we suspect that this change could be due to the effect of uremic toxins on hepatic uptake and/or efflux transporters. Using rat hepatocytes and microsomes as model proof of concept systems, we examined six uremic toxins, 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid (CMPF), indoxyl sulfate (IS), hippuric acid (HA), indole acetic acid (IA), guanidinosuccinic acid (GSA) and indoxyl-b-D-glucuronide (IG), for their effects on Ery uptake and metabolism. Ery and the metabolite N-demethyl-Ery were measured by LC/MS/MS. The uptake of Ery by rat hepatocytes was markedly inhibited by rifampin and digoxin, but not by quinidine, suggesting that Oatp2 plays a major role in the uptake of Ery. At 50 µM, CMPF significantly (p<0.05) reduced hepatocyte accumulation of Ery and N-demethyl-Ery. At higher concentrations (>200 µM), CMPF appears to also inhibit the enzymatic metabolism of Ery. In contrast, IS did not significantly inhibit the hepatocyte uptake of Ery even at the highest concentration (800 µM) tested, but reduced metabolite generation (p<0.001). The other uremic toxins, HA, IA, IG and GSA, did not affect either hepatic uptake or microsomal metabolism of Ery. CMPF, IS and HA were shown to not inhibit differential P-glycoprotein (P-gp) transport of Ery in cellular systems. Our results suggest that CMPF can directly inhibit the uptake of Ery by inhibiting Oatp2, while IS is more likely to inhibit the enzymatic metabolism of Ery.

Key words: chronic renal failure, drug distribution, drug transport, hepatic transport, hepatic uptake, hepatobiliary disposition, hepatobiliary transport, hepatocytes, transporters

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