期刊
CLINICAL PHARMACOLOGY & THERAPEUTICS
卷 87, 期 4, 页码 465-472出版社
WILEY
DOI: 10.1038/clpt.2009.247
关键词
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资金
- National Institutes of Health (NIH) [T32 GM07456, GM61390]
- Division of Research Resources, NIH [5-M01-RR-00079]
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR000079] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [U19GM061390, U01GM061390] Funding Source: NIH RePORTER
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 (CLH) 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, CLH 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 CLH of ER and the levels of uremic toxins.
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