Stereoselective pharmacokinetics of ketoprofen and ketoprofen glucuronide in end-stage renal disease: evidence for a 'futile cycle' of elimination.
OBJECTIVE
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.
Grubb
N G
NG
Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Roudebush Veterans Affairs Medical Center and, Wishard Memorial Hospital, Indianapolis, IN, USA.
Rudy
D W
DW
Brater
D C
DC
Hall
S D
SD
D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006801:Humans; D007660:Ketoprofen / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics*; D007676:Kidney Failure, Chronic / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis; D013237:Stereoisomerism; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; C044223:ketoprofen glucuronide; D007660:Ketoprofen