Pharmacokinetics and Metabolism of the Anti-Inflammatory Agent Voltaren

Abstract

Diclofenac sodium, the active substance of Voltaren®, is totally absorbed following both oral and rectal administration and is excreted, mainly in metabolised form, partly in the urine and partly in the bile. The extent of its biliary excretion varies from species to species. In the rat and the dog, diclofenac sodium is subject to enterohepatic circulation. In man, mainly hydroxylated metabolites are produced, which are excreted in the urine in the form of glucuronides accounting for roughly 60 % of the dose administered. Oral doses of 25 mg and 50 mg, given as enteric-coated tablets, lead to mean maximum plasma concentrations of approximately 0.5 μg/ml and 1.0 μg/ml, respectively, after about two hours. Four hours after administration of these doses, the levels still detectable in the plasma are equivalent to some 10 % of the maximum concentrations. Repeated oral doses ensure uniform bio-availability of the active substance. When diclofenac sodium is administered in therapeutic doses, 99.7 % of the concentration attained in the serum is bound to protein. Diclofenac sodium does not interfere with the protein binding of other drugs, such as tolbutamide, salicylates, warfarin, aceno-coumarol, or prednisolone, but the protein binding of diclofenac sodium itself can be significantly impaired by high doses of anionic drugs, such as salicylic acid. In the rat, simultaneous administration of diclofenac sodium (1 mg/kg i.v.) and salicylic acid in a dosage ratio of 1:20 leads to increased biliary excretion of diclofenac sodium but not to any significant change in its distribution in the various organs; the latter is influenced, however, by even higher doses of salicylic acid. In man, a relative decrease in the diclofenac sodium concentrations in the plasma is observed when 1000 mg acetylsalicylic acid is given concomitantly with 50 mg Voltaren: in relation to the values recorded in response to administration of 50 mg Voltaren alone, the maximum concentrations are reduced by 37 ®17% and the areas under the concentration curves by 33 ®14% [i® s(x),N=6].