Influence of indomethacin on the intrarenal uptake of gentamicin in endotoxemic rats

Abstract

Gentamicin is a commonly used antibiotic for the treatment of gram-negative-bacterial infections. Bacterial endotoxin is liberated during antibiotic therapy, and we have shown that endotoxemic animals accumulate more aminoglycosides in their renal parenchyma than normal animals. Vasoactive mediators, such as prostaglandins and thromboxanes, are released after endotoxin and are involved in inflammation. Indomethacin, a nonsteroidal anti-inflammatory drug known to inhibit the synthesis of these hormones, was infused intravenously as a bolus (3.0 mg/kg) or as a bolus followed by a continuous infusion (0.75 mg/kg per h) to rats given gentamicin. Levels of gentamicin in serum and kidney were increased 2 h post-antibiotic treatment in the endotoxemic animals. Renal function was not significantly disturbed. Indomethacin given as a bolus failed to correct the disturbed intrarenal pharmacokinetics of gentamicin induced by endotoxin. However, a bolus followed by continuous infusion of indomethacin resulted in low cortical and high papillary levels of antibiotic. These changes were correlated with the inhibition of prostaglandin synthesis from the kidney. These observations suggest an important role for prostaglandins in the interaction among endotoxin, aminoglycosides, and the kidney. Specific inhibitors of arachidonic acid metabolites should be investigated to further understand the mechanisms of this interaction.Several observations indicate a relationship between endotoxemia and impairment of renal function (5, 9). Studies from our laboratory revealed increased uptake of aminoglycosides in kidneys of animals suffering from pyelonephritis or receiving endotoxin (1-3). Synergistic toxicity of endotoxin and tobramycin was also seen in rabbit proximal tubular cells grown in primary cultures (V. Joly, M. G. Bergeron, G. Friedlander, Y. Bergeron, C. Amiel, and C. Carbon, Program Abstr. 28th Intersci. Conf. Antimicrob. Agents Chemother., abstr. no. 291, 1988). Endotoxin is known to disturb the hemodynamic status of the host, activate immunological and inflammatory processes, and act directly on organelles to induce cell injury. In response to endotoxin, vasoactive mediators such as prostaglandins and thromboxanes are released from blood cells and tissues and are responsible for inflammation and vasoconstriction-vasodilation cycles with subsequent lung, heart, and kidney injury (7).The aim of the present study was to evaluate a possible indirect influence of endotoxin upon the intrarenal uptake of gentamicin by blocking the liberation of prostaglandins with the use of indomethacin. Indomethacin is a nonsteroidal anti-inflammatory drug which is known to neutralize the enzyme cyclooxygenase, which catalyzes the catabolism of arachidonic acid into prostaglandins, thromboxanes, and prostacyclins. Indomethacin has also been shown in some experimental studies to improve circulatory status and survival (6).(These data were presented in part at the 26th Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La....

Pharmacologic basis for the treatment of pyelonephritis

“…The intrarenal levels of aminoglycosides [41][42][43][44][45][46] and vancomycin [47] were significantly increased following the injection of endotoxin in rats, whereas endotoxin had no effect on cephalothin [41]. Other factors such as old age are associated with lower levels of gentamicin in the renal tissue [48], whereas kidney levels of gentamicin [49] and tobramycin [50] are increased following a short period of fasting.…”

A Rat Model of Early Sepsis: Relationships between Gentamicin Pharmacokinetics and Systemic and Renal Effects of Bacterial Lipopolysaccharide Combined with Interleukin-2

“…15,18,19) Despite the fact that both CL cr and renal CL of GE were markedly reduced in LPSIL-2 rats, the value of total plasma CL during the treatment period was only marginally less due to a dominant contribution of nonrenal mechanisms in this group. Thus, the general view that the rate of GE elimination is determined mainly by GFR is challenged in this rat model of early sepsis.…”

“…after massive overdosing. 8,15,16) In the range of therapeutic steady-state concentrations, GE did not reduce CL cr (the marker of GFR) either in controls or LPSIL-2 rats. This is in contrast to its marked decrease due to the effect of LPSIL-2 alone.…”

“…16,20) It should be emphasized that significantly higher concentrations of GE were detected in the renal tissue homogenate from LPSIL-2-challenged rats, which agrees with earlier reports. 15,20) Biliary excretion of GE, which is a minor elimination route under physiological conditions, could also increase in septic rats. 21) Changes in renal function parameters observed in the early period following LPSIL-2 administration were comparable to those described by others after 1 mg/kg of LPS administered as an i.v.…”

“…15) Based on the available results, it is not possible to identify the nonrenal routes by which the drug is cleared from the plasma. In septic rats, the escape of the drug into the "third space" (pleural, peritoneal, intra-articular, pericochlear fluid etc.)…”