Pharmacokinetic Interaction in Rabbits between a New Anticonvulsant, DL-3-Hydroxy-3-ethyl-3-phenylpropionamide, and Phenytoin

Abstract

Abstract The effect of phenytoin on the disposition of DL-3-hydroxy-3-ethyl-3-phenylpropionamide (HEPP) has been studied in New Zealand white rabbits. Plasma HEPP levels decreased when the drug was administered with phenytoin. The area under the plasma concentration-time curve was reduced by 56.49% (from 43.23 ± 7.0 to 18.81 ± 2.03 μg h mL−1), the elimination half-life was also significantly (P<0.01) reduced (from 2.68 ± 0.35 to 1.04 ± 0.07 h) and the clearance was increased (from 0.35 to 0.81 L h−1 kg−1). In-vitro protein binding to bovine serum albumin (BSA) and plasma was evaluated by equilibrium dialysis. Plasma protein binding was low (between 33.69 and 37.43% at concentrations ranging from 6.25 to 100 μg mL−1). The compound binds preferentially to albumin with an association constant (Ka) of 3.81 times 103 M−1 at 37°C. The results suggest a pharmacokinetic interaction between phenytoin and HEPP, probably on the drug-metabolizing enzyme system in the liver.