The toxicokinetics of ketoprofen in Gyps coprotheres : toxicity due to zero-order metabolism

Abstract

In a safety study, Cape GriVon vultures (Gyps coprotheres) were dosed with ketoprofen at single doses of ~1 mg/kg (n = 5) and 5 mg/kg (n = 11). No toxicity was reported in the 1 mg/kg group, with the AUCinf, Vz and Cl being 10.42 g/ml h, 0.37 l/kg and 0.10 l/h kg, respectively. Toxicity occurred in the 5 mg/kg group, with 7 of the 11 birds dying. Clinical signs of toxicity included depression, loss of appetite and apparent coma. Animals died within 48 h of dosing. The AUCinf, Vz and Cl in the birds that survived were 52.26 g/ml h, 0.45 l/kg and 0.10 l/h kg, respectively. The AUCinf, Vz and Cl in the birds those died were 207.90 g/ml h, 0.26 l/kg and 0.02 l/h kg, respectively. Based on the increase in the AUCinf and Cmax in the birds that died, we surmise that toxicity resulted from saturation of the metabolic process. While the exact metabolic pathway remains unknown in these vultures, we believe that toxicity may be due to pharmacogenomic diVerences in the cytochrome P450 pathway.