Non-linear hepatic first-pass metabolism of salicylamide in dogs after portacaval transposition.

The effect of the rate of input of salicylamide into the portal vein of dogs on the clearance and bioavailability of the drug was examined. The four dogs had undergone portacaval transposition so that a hindlimb infusion delivered the drug directly and only into the liver. On separate occasions, salicylamide, 20 mg/kg, was infused into a hindlimb vein at three different rates, the duration of each infusion was 3, 10, and 30 min. Simultaneously, to measure the bioavailability, 14C-salicylamide was infused at the same rate into a forelimb vein. As the duration of the infusion was increased from 3 to 30 min, the clearance of salicylamide increased significantly from 1.05 +/- 0.21 (mean +/- SD) to 1.57 +/- 0.38 L/min and the half-life decreased significantly from 14.66 +/- 3.60 to 9.09 +/- 2.42 min. Bioavailability decreased from 0.84 +/- 0.11 to 0.61 +/- 0.61, but the differences were not statistically significant. As predicted for a drug that has nonlinear clearance and bioavailability, the rate of infusion of salicylamide affects the values of these parameters.