Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end‐stage renal disease: evidence for a ‘futile cycle’ of elimination

• Published in: British journal of clinical pharmacology Vol. 48; no. 4; pp. 494 - 500
• Main Authors: GRUBB, N. G, RUDY, D. W, BRATER, D. C, HALL, S. D
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-10-1999; Blackwell Science; Blackwell Science Inc
• Subjects: acyl glucuronide; Adult; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Anti-Inflammatory Agents, Non-Steroidal - metabolism; Anti-Inflammatory Agents, Non-Steroidal - pharmacokinetics; Area Under Curve; Biological and medical sciences; Bones, joints and connective tissue. Antiinflammatory agents; Chromatography, High Pressure Liquid; enantiomers; Female; futile cycle; haemodialysis; Half-Life; Humans; ketoprofen; Ketoprofen - administration & dosage; Ketoprofen - analogs & derivatives; Ketoprofen - metabolism; Ketoprofen - pharmacokinetics; Kidney Failure, Chronic - metabolism; Male; Medical sciences; Middle Aged; Original; Pharmacology. Drug treatments; Renal Dialysis; Stereoisomerism; Time Factors; Kidney disease; Human; Prostaglandin-endoperoxide synthase; Urinary system disease; Enzyme; Hemodialysis; Metabolite; Single dose; Elimination; Oral administration; Enzyme inhibitor; Terminal stage; Metabolism; Glucuroconjugate; Ketoprofen; Isomer; Non steroidal antiinflammatory agent; Multiple dose; Stereoselectivity; Extrarenal dialysis; Renal failure; Arylpropionic acid derivatives; Oxidoreductases; Pharmacokinetics
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.1999.00046.x

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.