Effect of diet and gavage on the dose- and dose-mode-dependent absorption and metabolism of bidisomide in rat

1. The metabolism of bidisomide was investigated to examine how dose and mode of drug administration (i.e. diet admixture versus oral solution) affect the absorption and metabolism of bidisomide in the toxicity studies. 2. After dietary admixture, bidisomide was more absorbed and less metabolized at the higher doses. Reduced metabolism at the high doses resulted from saturation of stereospecific formation of the N-desisopropyl-arylhydroxy bidisomide (NDABD) metabolite. 3. The rat-specific NDABD metabolite was formed only from (-)-bidisomide on incubation with rat liver microsomes. 4. After oral solution dosing, absorption was increased and metabolism reduced compared with the dietary admixture. 5. After 24-h infusion, plasma concentrations of radioactivity were approximately dose-proportional. However, the concentrations in the liver were similar at the 200 and 400?mg/kg doses due to saturation of liver uptake of the NDABD metabolite.