Clorazepate Dipotassium and Diazepam in Renal Insufficiency: Serum Concentrations and Protein Binding of Diazepam and Desmethyldiazepam

Abstract

Five patients with chronic renal failure on maintenance hemodialysis and 5 healthy matched controls received single 20-mg i.v. doses of clorazepate dipotassium. Clearance of pharmacologically active unbound desmethyldiazepam was reduced in renal fialure patients as opposed to controls, and free fraction in serum was greater. Since desmethyldiazepam distribution was reduced in renal patients, elimination half-life was actually shorter than in controls (36 vs. 57 h). In 10 dialysis patients receiving chronic diazepam treatment (5-15 mg/day), steady-state concentrations of diazepam (56 ng/ml) and desmethyldiazepam (77 ng/ml) were significantly lower than in age- and weight-matched controls receiving similar doses (189 and 216 ng/ml, respectively). After correction for the higher free fractions of both compounds in renal patients as opposed to controls, steady-state concenrrations of unbound drug were similar between groups. Interpretation of kinetic variables and steady-state serum concentrations of extensively protein-bound drugs requires consideration of alteratins in protein binding that may occur in disease states.