Pharmacokinetics of tilidine in terminal renal failure

The aim of the present study was to investigate the pharmacokinetics of til idine and its metabolites during the dialysis procedure and in the dialysis -free interval. Tilidine is a prodrug that is metabolized presystemically i nto the active metabolite nortilidine. Nortilidine is degraded thereafter t o bisnortilidine and several polar metabolites. Nine patients with a creati nine clearance < 5 ml/min were treated in a crossover design with single or al doses of 1.5 mg/kg on the day of dialysis (dialysis performed from 3 to 6 hours after drug administration) and on a day in the dialysis-free interv al. Blood samples were taken frequently and analyzed for tilidine, nortilid ine, and bisnortilidine. Drug and metabolite concentrations were also measu red in aliquots of dialysate collected during dialysis. Only negligible amo unts of tilidine, nortilidine, and bisnortilidine (about 0.9% of the dose) were recovered from the dialysate. The pharmacokinetics of nortilidine and its inactive metabolite bisnortilidine was not affected by dialysis. The pr esystemic apparent clearance of the prodrug tilidine was decreased signific antly during the dialysis-free interval. A significant decrease of the rate of elimination and an increase of the AUC of bisnortilidine were observed if these parameters were compared with data obtained from healthy volunteer s. The plasma concentrations of nortilidine were comparable in patients and normal volunteers. Thus, a reduction of the dose of tilidine in patients w ith severely impaired kidney function seems not to be required. Tilidine an d its metabolites cannot be removed from the body by dialysis. Journal of C linical Pharmacology, 2001;41:79-84 (C) 2001 the American College of Clinic al Pharmacology.