Pharmacokinetics and Metabolism of Diclofenac Sodium in Yucatan Miniature Pigs

Abstract

The pig has been suggested as an animal model in biomedical research because of its physiological similarity to man. Therefore, the pharmacokinetics and metabolism of diclofenac sodium (Voltaren) were studied in four Yucatan minipigs after intravenous administration of 25 and 50 mg and oral administration of 50 mg in a solution of 50 mL buffer, 50 mL water, and 200 mL water, and the results compared to historical data in man. The absolute bioavailability after oral administration of 50 mL buffer, 50 mL water, and 200 mL water solutions were 107, 97, and 109%, respectively, compared to approximately 50% in man. The total plasma clearance in minipigs was fivefold slower than in humans (57 ± 17 vs 252 ± 54 mL/hr/kg). The plasma levels of the metabolites 4′-hydroxy, 5-hydroxy, 3′-hydroxy, 4′,5-dihydroxy, and 3′-hydroxy-4′-methoxy diclofenac were considerably lower in minipigs than in man after both iv and oral administration. These results suggest slower metabolism and/or enterohepatic recirculation of the parent drug in minipigs. The volume of distribution of the central compartment was 40% less in humans than in pigs (39 vs 67 mL/kg). The terminal half-lives of the parent drug were similar in pigs (2.4 hr) and humans (1.8 hr). The rate of oral drug absorption increased in the order of 50 mL aqueous, 200 mL aqueous, and 50 mL buffered solutions (K _a = 0.52±0.11, 0.59±0.13, and 1.2±0.7 hr⁻¹, respectively). These trends are similar in man and suggest that both buffering and intake volume can affect diclofenac absorption. Possible reasons for these results include the pH-dependent solubility of this drug and the effect of volume on gastric emptying.