INCREASED RENAL UPTAKE OF GENTAMICIN IN ENDOTOXEMIC RATS RECEIVING CONCOMITANT THROMBOXANE A(2) ANTAGONIST THERAPY

This report describes the effects of endotoxin and a thromboxane recep tor antagonist, L-655,240, on kidney function and the intrarenal pharm acokinetics of aminoglycosides. The rationale for these studies was th at 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 sho wn to increase the renal uptake of gentamicin, we investigated the pos sibility that thromboxane antagonists might interfere with the nephrot oxic potential of both substances. A decrease in the volume of distrib ution and an increase in the intracortical concentrations of gentamici n were observed in animals given endotoxin. Compared with, animals giv en 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-6 55,240 alone did not modify gentamicin pharmacokinetics but did decrea se p-aminohippuric acid secretion. Thromboxane antagonists in the cont ext of endotoxemia increase intrarenal uptake of aminoglycosides. If t hese 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.