Renal handling and effects of S(+)‐ibuprofen and R(–)‐ibuprofen in the rat isolated perfused kidney

Cox, P. Gerard; Moons, W. M.; Rüssel, Frans G. M.; Ginneken, C. A. M. Van

doi:10.1111/j.1476-5381.1991.tb09824.x

Cited by 12 publications

(8 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a result, elevated levels of (S)-ibuprofen arising from the slower clearance and the concomitant metabolic activation may exacerbate renal ischaemia through the accentuated blockage of cyclooxygenase [15]. This premise is corroborated by a recent report [16] which indicated that, in perfused rat kidney, (S)-ibuprofen with concentrations as low as 0.25 jg ml-' was able to cause a decrease in urinary flow, glomerular filtration rate and electrolyte excretion.…”

Section: Discussionsupporting

confidence: 72%

Stereoselective disposition of ibuprofen in patients with compromised renal haemodynamics.

Chen

1995

Brit J Clinical Pharma

View full text Add to dashboard Cite

1 The primary aim of this study was to assess the impact of renal haemodynamics on the pharmacokinetic behaviour of ibuprofen enantiomers. Thirty-two patients and ten age-matched healthy volunteers participated in this study. These patients had at least one of the following risk factors for cardiovascular disorders: hypertension, diabetes mellitus, hyperlipidaemia and hyperuricaemia with or without consequent complications such as coronary artery disease, congestive heart failure, cerebral vascular disease, and chronic renal failure. Renal function in these patients was thus characterized by unstable renal haemodynamics that might render them susceptible to ibuprofen-incurred renal damage. 2 Each subject received a single oral dose of 800 mg of racemic ibuprofen.The pharmacokinetic parameters of (S)-and (R)-ibuprofen, t/2 (S), t1/2(R), AUC(s), AUC(R), V/F(R), and CL/F(R), for each individual were determined from respective plasma concentration-time curves. To assess the effect of individual clinical conditions on the disposition of ibuprofen enantiomers, the arithmetic means of these pharmacokinetic parameters for each disease group were compared with those of the healthy volunteers by a t-test.3 All of these disease groups showed elevated AUC(s) and higher (S)/(R) AUC ratios. These disease states along with gender and age were analyzed by multiple linear regression to discern significant factors for elevating AUC(s). Of these, advanced age (P = 0.02) and hypertension (P = 0.03) were identified as independent factors contributiong to AUC(s) increase in this population. Thus, patients with these two clinical conditions are at particular risk from the adverse renal effect of ibuprofen.

show abstract

Section: Discussionsupporting

confidence: 72%

Stereoselective disposition of ibuprofen in patients with compromised renal haemodynamics.

Chen

1995

Brit J Clinical Pharma

View full text Add to dashboard Cite

show abstract

“…Although stereoselective clearance has been discussed in the literature, reports concerning renal handling of ibuprofen enantiomers seemed to be contradictory. In a model of isolated perfused rat kidney, enantioselective excretion of ibuprofen isomers was observed in the research carried out by Ahn et al (1991) but not by Cox et al (1991). One possible explanation for this contradictory result was that enantiomer-to-enantiomer interaction contributed to the stereoselective handling of ibuprofen enantiomers because results obtained by Ahn were derived from racemate administration, whereas the single enantiomer was administered separately in the Cox research.…”

Section: Excretionmentioning

confidence: 52%

Enantioselective Pharmacokinetics of Ibuprofen and Involved Mechanisms

Hao

Wang²

2005

Drug Metabolism Reviews

View full text Add to dashboard Cite

Although dexibuprofen (S-ibuprofen) was marketed in Austria and Switzerland, the racemate at various formulations is still extensively used worldwide, and there are no indications that the racemate will be replaced by the single enantiomer. Thus, elucidation of the characteristics and involved mechanisms of the chiral pharmacokinetics of racemic ibuprofen is of special importance for the understanding of the pharmacological and toxicological consequences, and for prediction of the clinically potential drug interactions and influence of the pathological states. Stereoselective pharmacokinetics and metabolism are common features for chiral nonsteroidal antiinflammatory drugs (NSAIDs) and especially for 2-arylpropionic acid derivatives characterized with a chiral center adjacent to the carboxyl group. Although the enantioselective pharmacokinetic characteristics of different NSAIDs should be treated case by case, they share similar mechanisms underlying the protein binding, metabolism and chiral inversion. Ibuprofen was the most extensively researched drug in terms of chiral characteristics and mechanisms. Therefore, elucidation of the mechanisms derived from research on ibuprofen may provide better understanding and prediction of other chiral drugs. This article attempts to elucidate the chiral pharmacokinetics and involved mechanisms of ibuprofen in comparison with other NSAIDs based on recent developments. Topics on history of ibuprofen, enantioselective analysis method, absorption, protein binding, conventional metabolism, metabolic chiral inversion, gene polymorphism, and biochemical developments were included. It is worth mentioning that some underlying biochemical mechanisms, especially for the metabolic chiral inversion and ethnic differences still remain to be seen. Further research is required to develop human-resourced researching model and to provide more evidence concerning the site of inversion, species variation, CYP450 gene polymorphisms, and biochemical mechanisms.

show abstract

“…However, the major metabolite of phenacetin is acetaminophen, which accumulates within the papillae (95). Accumulation of NSAIDs in animal renal tissue has been demonstrated for a variety of NSAIDs, but studies do not specify whether there were differences among tissue compartments such as the papillae (21)(22)(23).…”

Section: Analgesic-associated Nephropathymentioning

confidence: 96%

Renal Toxicity of the Nonsteroidal Anti-Inflammatory Drugs

Murray¹,

Brater²

1993

Annu. Rev. Pharmacol. Toxicol.

272

150

View full text Add to dashboard Cite

NSAIDs pose little threat of renal insult in normal, healthy persons at therapeutic dosages. However, NSAID administration to susceptible persons may cause decrements in renal plasma flow and glomerular filtration rate within hours. Such acute noxious renal effects are mediated by products of arachidonic acid metabolism. Precipitous decrements in glomerular filtration and renal ischemia, manifested by increased serum creatinine and urea nitrogen, are possible. However, these effects are usually fully reversible with prompt discontinuation of the offending NSAID. Risk factors for the development of these acute renal effects are known. Acute interstitial nephritis with or without nephrotic syndrome is a rare form of renal toxicity that typically occurs between 2-18 months of use. Renal impairment may be so severe as to require temporary hemodialysis; however, renal function usually returns to normal upon discontinuation of the NSAID. The mechanism of acute interstitial nephritis is presumed to be of allergic origin but could also be caused by a reactive metabolite. Fenoprofen use appears to be associated with a much higher risk for its development. In contrast to the acute effects of NSAIDs, irreversible, analgesic-associated nephropathy manifested by papillary necrosis and chronic interstitial nephritis may occur following months to years of high doses of analgesic mixtures. The mechanism by which combination analgesics produce this form of renal injury is unknown and could be either a result of medullary ischemia or a direct effect of a reactive metabolite. An important issue to be resolved is the relationship between the acute, reversible, prostaglandin-mediated renal effects of the NSAIDs and chronic, irreversible destruction, if such a relationship exists. Theoretically, continual or repeated decrements in renal function in patients with predisposing risk factors could cause or contribute to progressive deterioration in renal function. Elevations in blood pressure or interference with the effects of antihypertensive medications could theoretically also contribute to long-term renal deterioration. In addition to renal syndromes caused by NSAIDs that result in renal impairment, other transient effects on electrolyte and water metabolism may also occur. Reduced secretion of sodium may result in formation of edema, exacerbation of heart failure, or increased blood pressure. Hyporeninemic-hypoaldosteronism may produce hyperkalemia. Finally, reduced excretion of water has rarely caused hyponatremia. It has been suggested that NSAIDs may be renoprotective in patients with nephrotic syndrome. Others have suggested that sulindac is "renal-sparing" because of a unique metabolic pathway that supposedly limits the exposure of the kidney to the active sulfide metabolite.(ABSTRACT TRUNCATED AT 400 WORDS)

show abstract

Renal handling and effects of S(+)‐ibuprofen and R(–)‐ibuprofen in the rat isolated perfused kidney

Cited by 12 publications

References 23 publications

Stereoselective disposition of ibuprofen in patients with compromised renal haemodynamics.

Stereoselective disposition of ibuprofen in patients with compromised renal haemodynamics.

Enantioselective Pharmacokinetics of Ibuprofen and Involved Mechanisms

Renal Toxicity of the Nonsteroidal Anti-Inflammatory Drugs

Contact Info

Product

Resources

About