Affiliation:
1. Laboratoire et Service d'Infectiologie, Centre de Recherche du Centre Hospitalier de l'Université Laval, Québec, Canada.
Abstract
This report describes the effects of endotoxin and a thromboxane receptor antagonist, L-655,240, on kidney function and the intrarenal pharmacokinetics of aminoglycosides. The rationale for these studies was that thromboxane antagonists may eventually be used in combination with aminoglycosides in patients with gram-negative sepsis and endotoxemia. As aminoglycosides are nephrotoxic and endotoxin has already been shown to increase the renal uptake of gentamicin, we investigated the possibility that thromboxane antagonists might interfere with the nephrotoxic potential of both substances. A decrease in the volume of distribution and an increase in the intracortical concentration of gentamicin were observed in animals given endotoxin. Compared with animals given endotoxin alone, those which received endotoxin plus L-655,240 had significant accumulation of gentamicin in the renal cortex and medulla, as determined by the area under the concentration-time curve, and a significant reduction in the total clearance of the antibiotic (P < 0.05). This difference in uptake could not be attributed to hypotension or changes in the glomerular filtration rate or renal plasma flow. L-655,240 alone did not modify gentamicin pharmacokinetics but did decrease p-aminohippuric acid secretion. Thromboxane antagonists in the context of endotoxemia increase intrarenal uptake of aminoglycosides. If these compounds are to be used as therapeutic agents when endotoxin is present, their influence on renal handling of nephrotoxic drugs needs to be considered. Multiple-dosing regimens deserve investigation.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Reference50 articles.
1. Thiol modification in H202- and thromboxane-induced vaso- and bronchoconstriction in rat perfused Iung;Atzori L.;J. Appl. Physiol.,1991
2. Gentamicin-induced Iysosomal phospholipidosis in cultured rat fibroblasts: quantitative ultrastructural and biochemical study;Aubert-Tulkens G.;Lab. Invest.,1979
3. Prolonged endotoxemia enhances the renal injuries induced by gentamicin in rats;Auclair P.;Antimicrob. Agents Chemother.,1990
4. Roles for thromboxane A2 and leukotrienes in endotoxininduced acute renal failure;Badr K. F.;Kidney Int.,1986
5. Protection against gentamicin-induced early renal alterations (phospholipidosis and increased DNA synthesis) by coadministration of poly-L-aspartic acid;Beauchamp D.;J. Pharmacol. Exp. Ther.,1990
Cited by
4 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献