Toxicokinetics of cotyledoside following intravenous administration to sheep

Cotyledoside, a bufadienolide cardiac glycoside, was administered intravenously to sheep in 2 studies. In experiment 1, sheep (n = 4) received 0.0135 mg/kg daily on 5 consecutive days and in the 2nd experiment, sheep (n = 4) received 0.027 mg/kg as a single dose. jugular blood was collected at different time intervals and kinetic parameters were determined. The data fitted a 1-compartmental model. In both experiments a short half-life (t1/2) and mean residence time (MRT), a relative small volume of distribution (Vd(ss)) and rapid clearance were calculated. In the 1st experiment, t1/2 and MRT increased significantly (P < 0.007) from Day (D) 0 to D 4. It is suggested that the rapid decline in plasma cotyledoside concentrations in sheep denotes rapid distribution of cotyledoside to the tissues or extracellular spaces and possible accumulation at the biophase.