Gender-related differences in the pharmacokinetics of tolmetin in the rat

Tolmetin is a non-steroidal anti-inflammatory drug (NSAID) that is used in the treatment of arthritis and osteoarthritis. Its mechanism of action, as other NSAIDs, is by inhibition of prostaglandin synthesis. Despite the fact of gender-related differences in the pharmacokinetics (PK) and pharmacodynamics (PD) of some NSAIDs, tolmetin PK have only been evaluated in males at present. We therefore compared tolmetin PK in male and female rats. Animals received an oral 10 mg/kg tolmetin dose under fasting conditions and blood samples were drawn at different times over a 4 h period. Tolmetin concentration in whole blood was determined by HPLC. Tolmetin blood levels increased rapidly reaching a peak of 13.5 ±3.1 μg/ml in 0.22 ± 0.09 h in males and 13.4 ±2.1 μg/ml in 0.33 ±0.09 h in females. Tolmetin was eliminated more rapidly in males with a half-life of 0.9 ±0.09 h, compared to a value of 3.3 ±0.54 h in females. As a result, drug bioavailability was higher in females, AUC values being 15.4 ±2.74 and 28.2 ±4.35 μg/h/ml. Our results confirm PK differences among genders for NSAIDs in experimental animals. Further investigation is required to establish the clinical impact of such differences in humans.