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Diclofenac is well absorbed following oral dosing but, with administration of the enteric-coated preparation, the time to peak plasma concentration can be variable.

There is some presystemic elimination but about 60% of the oral dose reaches the systemic circulation. A linear increase in AUC with dose has been reported over the range 25 - 150 mg in man. Like many other NSAIDs, diclofenac is highly bound to plasma protein, mainly albumin, and the degree of binding has been shown to be >99.5%.

Data on tissue penetration in man are scarce, but in mice the highest concentrations were found in liver, bile and kidney with only a small amount in the brain and spinal cord. Substantial concentrations of drug are attained in synovial fluid, which is the proposed site of action for NSAIDs.

Diclofenac entered the synovial fluid quickly, since the mean 2 hr synovial concentration was approximately 2/3 that in plasma (197 and 293 µg/l respectively) and diclofenac persisted in the synovial fluid much longer (mean 7 hr concentration 205 µg/l) compared with plasma (52 µg/l). In a study of six mothers treated for 1 week with 100 mg diclofenac sodium daily, none of the 59 milk samples contained detectable amounts of unchanged drug (limit of detection 10 µg/l).

A comparison of diclofenac pharmacokinetics in young volunteers with rheumatoid arthritis showed a reduction in the peak plasma concentration in the latter group but no significant change in AUC or elimination half life.

Concentration-effect relationships have been established for total bound, unbound and synovial fluid diclofenac concentrations.

Metabolism and Elimination

Diclofenac is extensively metabolized by animals and man to a range of phenolic compounds, excreted as their glucuronide or sulphate conjugates. In man the major metabolite is the 4'-hydroxy compound and 20 - 30% of an oral dose is excreted in this form in the urine with a further 10 - 20% in the bile. Free diclofenac accounts for < 1% of the dose in urine.

The excretion of conjugates may be related to renal function. Conjugate accumulation occurs in end-stage renal disease; however, no accumulation is apparent upon comparison of young and elderly individuals. Dosage adjustments for the elderly, children or for patients with various disease states (such as hepatic disease or rheumatoid arthritis) may not be required.

Significant drug interactions have been demonstrated for aspirin (acetylsalicylic acid), lithium, digoxin, methotrexate, cyclosporin, cholestyramine and colestipol.