The influence of renal function on the pharmacokinetics of unchanged and acyl-glucuroconjugated ketoprofen enantiomers after 50 and 100 mg racemic ketoprofen.

1. To study the effect of renal dysfunction on the pharmacokinetics of ketoprofen (KT), and the possibility of saturation of clearance with elevation of dose, single 50 and 100 mg doses of racemic ketoprofen were administered in a cross-over fashion to seven patients (creatinine clearance, CLCR, 6-72 ml min-1). 2. The stereospecific disposition kinetics of KT enantiomers and their acyl-glucuronide conjugates (KTconj) were determined in plasma and urine for 24 h post-dose. 3. Decreased renal function was associated with a reduced KT oral clearance (CLO) and terminal elimination rate constant (lambda z). Renal clearance of KT conj (CLrconj) was reduced with diminished renal function. 4. Following both 50 and 100 mg doses, there was significant stereoselectivity in the AUC of KT (mean S/R, 0.87 and 0.83, respectively), the AUC of KTconj (mean S/R, 3.4 and 5.2, respectively) and the cumulative urinary excretion of KTconj (mean S/R, 2.1 and 2.2, respectively). The stereoselectivity in renal dysfunction in contrast with the observations previously made in healthy subjects may suggest a disease-related process. 5. CLO remained constant after increasing the dose, indicating linearity in the pharmacokinetics of KT despite reduced CLCR. CLrconj, however, was significantly reduced after the 100 mg dose suggestive of saturation of the urinary clearance and existence of a compensatory pathway. 6. Renal impairment reduces CLrconj and this appears to be the rate-limiting step for clearance of KT due to the observed stronger correlations of CLO with CLrconj than with CLCR. 7. Dose reduction of ketoprofen is indicated only for patients with CLCR < 20 ml min-1.