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.

Figure 1

Plasma concentration-time profiles of R-ketoprofen (○), S-ketoprofen (○), R-ketoprofen glucuronide (□) and S-ketoprofen glucuronide after (▪). Panel a, single 50 mg oral dose of ketoprofen (n = 6). Panel b, 50 mg ketoprofen oral dose following 8 days of dosing with 50 mg three times daily (n = 6).