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1. The kinetics of diclofenac (I) and five of its metabolites (II-VI) were investigated in three healthy volunteers and in six patients. Compounds I-VI were measured by capillary column gas chromatography in plasma and urine. 2. After a single 100 mg dose of diclofenac sodium to volunteers, the drug was absorbed rapidly and showed peak plasma levels of 10-12 nmol/g. The maximum concentrations of five metabolites were comparatively low (0.36-2.94 nmol/g). The mono- and dihydroxy metabolites (II-V) had apparent terminal half-lives similar to that of I (1-3 h), but the hydroxymethoxy metabolite (VI) had a half-life of about 80 h. Renal elimination of VI within 96 h was about 1% of dose and that of I-VI was 36% (free plus conjugated). 3. Following daily treatment with 2 x 75 mg of an experimental sustained release formulation to patients for 6-10 months, steady-state trough concentrations of I-V in plasma were low (average values: 0.23-0.57 nmol/g). The mean trough concentration of VI was comparatively higher at 3.69 +/- 0.91 nmol/g presumably reflecting its accumulation. Despite this it is unlikely to contribute to the drug's therapeutic activity, since it has been shown in laboratory tests to be devoid of anti-inflammatory activity.

In humans, diclofenac sodium (Voltaren), a potent anti-inflammatory agent, is metabolized to a large extent by hydroxylation and conjugation to glucuronides and sulfates. This paper describes a procedure whereby unchanged diclofenac as well as all known hydroxylated metabolites (3'-hydroxy-, 4'-hydroxy-, 5-hydroxy- and 4',5-dihydroxy-diclofenac) are determined quantitatively in the same biological sample. The procedure is based on extractive alkylation and gas chromatography with capillary columns and electron capture detection. The method has been applied to analyse urine samples of volunteers treated with single doses of diclofenac sodium.