PHARMACOKINETICS AND HEPATOTOXICITY OF DICLOFENAC USING AN ISOLATED-PERFUSED RAT-LIVER

Pharmacokinetics and hepatotoxicity of diclofenac was studied in a rec irculating model of isolated perfused rat liver. Ten male Sprague-Dawl ey rat (weighing 230-330 g) livers were perfused for 2 h with 250 mt K rebs-Henseleit bicarbonate buffer that contained 10.75 mg (group A, a = 5) and 1.075 mg (group B, n = 5) of diclofenac (approximately 100 an d 10 times the therapeutic dose in man, respectively). Samples were co llected from the efflux at regular time intervals for the determinatio n of diclofenac concentrations by a high performance liquid chromatogr aphy (HPLC) method. Pharmacokinetic analyses were carried out using a computer program. To establish viability of the liver and toxicity of the drug, enzyme activity measurements of lactate dehydrogenase (LDH), aspartate aminotransferase (SGOT) and piruvate aminotransferase (SGPT ) were performed by a spectrophotometric method. Oxygen consumption wa s also recorded during the entire perfusion period. Both groups presen ted bicompartmental kinetics. Concentration profiles showed that group B had a better metabolizing capacity, reflected in a 85.54 +/- 37.05 min half-life, a 0.52 +/- 0.19 mt min(-1) g(-1) liver clearance and a 0.517 +/- 0.188 extraction ratio, compared to group A, which presented a 123.95 +/- 88.13 min half-life. a 0.1164 +/- 0.067 mt min(-1) g(-1) liver clearance (P < 0.002) and a 0.116 +/- 0.680 extraction ratio (P < 0.002). LDH activity showed a significant increase in group A at 90 min in comparison with the control group, while in group B this incre ase was significantly higher at 10 min (P < 0.004). The aminotransfera se levels did not show a significant increase. According to these resu lts, diclofenac would not have a direct hepatotoxic effect, even at do ses 100 times higher than therapeutic ones.