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

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 19.4 ± 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.