Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end-stage renal disease: evidence for a 'futile cycle' of elimination.

Abstract

AIMS:

To assess if futile cycling of ketoprofen occurs in patients with decreased renal function.

METHODS:

Ketoprofen was administered to six haemodialysis-dependent patients with end-stage renal disease as single (50 mg) or multiple doses (50 mg three times daily, for 7 days). Plasma and dialysate concentrations of the unconjugated and glucuronidated R- and S-enantiomers of ketoprofen were determined using h.p.l.c. following the single and multiple dosing.

RESULTS:

The oral clearance was decreased and terminal elimination half-lives of R- and S-ketoprofen and the corresponding acyl glucuronides were increased in functionally anephric patients compared with healthy subjects. In contrast with the R-isomers, S-ketoprofen and S-ketoprofen glucuronide exhibited an unexpected accumulation (2.7-3. 8 fold) after repeated dosing achieving S:R ratios of 3.3+/-1.7 and 11.2+/-5.3, respectively. The plasma dialysis clearances for R- and S-ketoprofen glucuronides were 49.4+/-19.8 and 39.0+/-15.9 ml min-1, respectively, and 10.8+/-17.6 and 13.3+/-23.5 ml min-1 for unconjugated R- and S-ketoprofen.

CONCLUSIONS:

The selective accumulation of S-ketoprofen and its acyl glucuronide are consistent with amplification of chiral inversion subsequent to futile cycling between R-ketoprofen and R-ketoprofen glucuronide. Severe renal insufficiency, and possibly more modest decrements, results in a disproportionate increase in systemic exposure to the S-enantiomer which inhibits both pathologic and homeostatic prostaglandin synthesis.

• Authors: N G Grubb, D W Rudy, D C Brater, S D Hall
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 48 Issue 4 Pg. 494-500 (Oct 1999) ISSN: 0306-5251 [Print] England
• PMID: 10583018 (Publication Type: Clinical Trial, Comparative Study, Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• ketoprofen glucuronide
• Ketoprofen

Topics

• Adult
• Anti-Inflammatory Agents, Non-Steroidal (administration & dosage, metabolism, pharmacokinetics)
• Area Under Curve
• Chromatography, High Pressure Liquid
• Female
• Half-Life
• Humans
• Ketoprofen (administration & dosage, analogs & derivatives, metabolism, pharmacokinetics)
• Kidney Failure, Chronic (metabolism)
• Male
• Middle Aged
• Renal Dialysis
• Stereoisomerism
• Time Factors