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Hepatic Clearance, but Not Gut Availability, of Erythromycin Is Altered in Patients With End‐Stage Renal Disease
Author(s) -
Sun H,
Frassetto L A,
Huang Y,
Benet L Z
Publication year - 2010
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2009.247
Subject(s) - pharmacokinetics , dosing , bioavailability , volume of distribution , renal function , medicine , oral administration , end stage renal disease , erythromycin , pharmacology , clearance , kidney disease , endocrinology , chemistry , urology , disease , antibiotics , biochemistry
Nonrenal clearance of drugs can be significantly lower in patients with end‐stage renal disease (ESRD) than in those with normal renal function. Using erythromycin (ER) as a probe compound, we investigated whether this decrease in nonrenal clearance is due to reduced hepatic clearance (CL H ) and/or gut metabolism. We also examined the potential effects of the uremic toxins 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furan propanoic acid (CMPF) and indoxyl sulfate (Indox) on ER disposition. Route‐randomized, two‐way crossover pharmacokinetic studies of ER were conducted in 12 ESRD patients and 12 healthy controls after oral (250 mg) and intravenous (125 mg) dosing with ER. In patients with ESRD, CL H decreased 31% relative to baseline values (0.35 ± 0.14 l/h/kg vs. 0.51 ± 0.13 l/h/kg, P = 0.01), with no change in steady‐state volume of distribution. With oral dosing, the bioavailability of ER increased 36% in patients with ESRD, and this increase was not related to changes in gut availability. As expected, plasma levels of CMPF and Indox were significantly higher in the patients than in the healthy controls. However, no correlation was observed between CL H of ER and the levels of uremic toxins. Clinical Pharmacology & Therapeutics (2010) 87 4, 465–472. doi: 10.1038/clpt.2009.247