Pharmacokinetics of Diclofenac Sodium (Voltaren) And Metabolites in Patients with Impaired Renal Function

Abstract

The pharmacokinetics of the antirheumatic agent diclofenac sodium (Voltaren®) were studied in patients with impaired renal function. For this purpose, ^l4C-labelled diclofenac sodium was given in a single intravenous dose of 50 mg to patients who were suffering from varying degrees of renal dysfunction and whose glomerular filtration rates (GFR) ranged from 3 ml/min to 42 ml/min. Plasma concentrations of total ¹⁴C-labelled compounds, of unchanged active substance, and of two major metabolites were determined. The AUC_0-24h values of active substance were not increased in comparison with those of subjects with normal kidney function; on the other hand, the values for the total metabolites of diclofenac tended to be higher in the patients. But the rate of elimination of those metabolites still present after 24 hours was the same in the patients as in the healthy subjects. The theoretical steady-state concentration of total metabolites, calculated for repeated medication, was in the most extreme case of renal failure about four times higher than in normal subjects. This increase in concentration is, however, mostly due to conjugates of the drug or of its primary metabolites. Such conjugates are normally devoid of pharmacological activity, and a change in dosage regimen is therefore not indicated in patients with impaired renal function. The renal excretion of ¹⁴C-iabelled compounds correlates with endogenous creatinine clearance. Since, even in patients with the highest degree of renal dysfunction, the elimination rate from plasma was not reduced after the first 24 hours, a compensatory biliary excretion of conjugates presumably occurs.