EFFECT OF A HIGH-FAT MEAL ON THE BIOAVAILABILITY OF PHENYTOIN IN A COMMERCIAL POWDER WITH A LARGE PARTICLE-SIZE

The effect of a high-fat meal on the bioavailability of free acid phenytoin (DPH) from Hydantol powder with a large particle size (mean particle size, 190 mum) was investigated in four healthy male subjects. The drug was administered as a single oral 5 mg/kg dose of free acid DPH in the fasting state, with a low-fat meal, or with a high-fat meal using a crossover study design. Seven blood samples were collected over a 34-h period following drug administration, and the drug plasma concentrations were determined by GLC. In comparison with the fasting state results, the mean area under the plasma concentration-time curve up to infinity after administration (AUC0-infinity) and the peak plasma concentration (C(max)) of DPH from Hydantol powder significantly increased about 2-fold with the intake of the high-fat meal and about 1.5-fold with the intake of the low-fat meal. The elimination rate constant was not significantly different among the three treatments. The increased bioavailability with the high-fat meal probably resulted from accelerated dissolution of the poorly soluble Hydantol powder due to the stimulation of bile flow or delay of the gastric emptying time caused by the fat intake.