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

In a safety study, Cape Griffon vultures (Gyps coprotheres) were dosed with ketoprofen at single doses of similar to 1 mg/kg (n = 5) and 5 mg/kg (n = 11). No toxicity was reported in the 1 mg/kg group, with the AUC(inf), V(z) and Cl being 10.42 mu 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 AUC(inf), V(z) and Cl in the birds that survived were 52.26 mu g/ml h, 0.45 l/kg and 0.10 l/h kg, respectively. The AUC(inf), V(z) and Cl in the birds those died were 207.90 mu g/ml h, 0.26 l/kg and 0.02 l/h kg, respectively. Based on the increase in the AUC(inf) and C(max) 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 differences in the cytochrome P450 pathway.