A comparison of the effects of etodolac and ibuprofen on renal haemodynamics, tubular function, renin, vasopressin and urinary excretion of albumin and alpha-glutathione-S-transferase in healthy subjects: a placebo-controlled cross-over study.
BACKGROUND
Non-steroidal anti-inflammatory drugs (NSAIDs) are known to be potentially nephrotoxic agents. NSAIDs inhibit the enzyme cyclo-oxygenase and thereby block the prostaglandin synthesis in the kidneys. Cyclo-oxygenase exists in two isoforms (COX-1 and COX-2). It has been proposed that NSAIDs with preferential COX-2 selectivity have fewer renal side effects than drugs with preferential COX-1 selectivity. Etodolac is a relative selective inhibitor of COX-2, while ibuprofen has a higher potency against COX-1 than COX-2.


OBJECTIVE
In this study, we compared the effects of etodolac and ibuprofen on renal function, plasma renin, plasma arginine vasopressin and the urinary excretion of albumin and alpha-glutathione-S-transferase (alpha-GST).


METHODS
In a randomised, double-blind, three-way crossover study with placebo, we compared the effects of 2 weeks of treatment with ibuprofen and etodolac on renal haemodynamics [glomerular filtration rate (GFR), renal plasma flow (RPF) and filtration fraction (FF)], tubular function and plasma concentrations of the hormones renin (PRC) and arginine vasopressin (AVP) in 18 healthy subjects. In addition, we examined the effects on the urinary excretion of albumin and alpha-GST as markers of renal injury.


RESULTS
No differences were found between the three treatments, placebo, ibuprofen and etodolac, in the effects on GFR, RPF, FF, free water clearance, urinary output or fractional excretion of potassium and sodium. However, ibuprofen, in contrast to etodolac, caused a significant decrease in both lithium clearance (-16% versus placebo) and the fractional excretion of lithium (-17% versus placebo), suggesting an increase in the reabsorption in the proximal tubuli. PRC was reduced significantly by ibuprofen (-32% versus placebo) but not etodolac. None of the drugs changed AVP. Fourteen days of treatment with ibuprofen caused a significant decrease (-47% versus placebo) in the urinary excretion of alpha-GST, while no changes were seen after etodolac. None of the drugs changed the urinary excretion of albumin.


CONCLUSIONS
In conclusion, a 14-day administration of etodolac or ibuprofen in therapeutic doses did not affect the renal haemodynamics, the net excretion of electrolytes or the urinary excretion of albumin in healthy subjects. However, ibuprofen, in contrast to etodolac, caused a reduction in PRC, suggesting that COX-1 is involved in basal renin release in humans. Furthermore, ibuprofen decreased lithium excretion suggesting that COX-1 is involved in the re-absorption of sodium and/or water in the proximal tubuli. The reduction in the urinary excretion of alpha-GST by ibuprofen may be caused by an inhibition of the detoxification enzyme by ibuprofen. Overall the study indicates that only small differences in the effects of the two drugs on renal function in healthy subjects exist during a treatment period of 2 weeks.
Svendsen
K B
KB
kbs@dadlnet.dk
Bech
J N
JN
Sørensen
T B
TB
Pedersen
E B
EB
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001127:Arginine Vasopressin / Q000097:blood; D003404:Creatinine / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D004311:Double-Blind Method; D017308:Etodolac / Q000494:pharmacology*; D005260:Female; D005919:Glomerular Filtration Rate; D005982:Glutathione Transferase / Q000652:urine; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007052:Ibuprofen / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects; D008297:Male; D012083:Renin / Q000097:blood
D000894:Anti-Inflammatory Agents, Non-Steroidal; D001127:Arginine Vasopressin; D017308:Etodolac; D003404:Creatinine; D005982:Glutathione Transferase; D012083:Renin; D007052:Ibuprofen