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Drug Metabolism and Disposition Fast Forward
First published on July 30, 2004; DOI: 10.1124/dmd.104.000521

0090-9556/04/3211-1239-1246$20.00
DMD 32:1239-1246, 2004

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EFFECTS OF UREMIC TOXINS ON HEPATIC UPTAKE AND METABOLISM OF ERYTHROMYCIN

Hong Sun, Yong Huang, Lynda Frassetto, and Leslie Z. Benet

Department of Biopharmaceutical Sciences (H.S., Y.H., L.Z.B.), Division of Clinical Pharmacology and Experimental Therapeutics (H.S.); and Department of Medicine and General Clinical Research Center (L.F.), University of California, San Francisco, California

Hepatic clearance of erythromycin (Ery) is significantly reduced in patients with end stage renal disease. 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-ß-D-glucuronide (IG), for their effects on Ery uptake and metabolism. Ery and the metabolite N-demethyl-Ery were measured by liquid chromatography/tandem mass spectrometry. 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 not to inhibit differential P-glycoprotein transport of Ery in cellular systems. Our results suggest that CMPF can directly inhibit the uptake of Ery by inhibiting Oatp2, whereas IS is more likely to inhibit the enzymatic metabolism of Ery.

Address correspondence to: Dr. Leslie Z. Benet, Professor, Department of Biopharmaceutical Sciences, University of California San Francisco, 533 Parnassus, Room U-68, San Francisco, CA 94143-0446. E-mail: benet{at}itsa.ucsf.edu




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