Pharmacokinetics of diclofenac and five metabolites after single doses in healthy volunteers and after repeated doses in patients.
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.
Degen
P H
PH
Research and Development Department, CIBA-GEIGY Ltd., Basle, Switzerland.
Dieterle
W
W
Schneider
W
W
Theobald
W
W
Sinterhauf
U
U
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D001711:Biotransformation; D003692:Delayed-Action Preparations; D004008:Diclofenac / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D006207:Half-Life; D006801:Humans; D008297:Male; D008875:Middle Aged; D015394:Molecular Structure
D003692:Delayed-Action Preparations; D004008:Diclofenac