ENHANCEMENT OF THE ORAL BIOAVAILABILITY OF PHENYTOIN BY N-ACETYLATIONAND ABSORPTIVE CHARACTERISTICS

To improve the absorbability of phenytoin (DPH), a prodrug, N-acetyl-D PH (EDPH), was synthesized, and the absorptive characteristics and pha rmacokinetics of the prodrug were evaluated in rats. EDPH was rapidly hydrolyzed to DPH in the intestinal fluid and the mucosa (rate constan t, 0.055 and 0.169 min(-1), respectively). The plasma concentrations o f DPH after intravenous dosing of EDPH declined in a biexponential man ner, although two different elimination patterns were observed in thes e rats. When dosed orally (25 mg/kg, DPH equivalent), the plasma level s of DPH converted from the prodrug were significantly higher and more sustained than those after DPH alone, giving bioavailability 11.4 (ra pid decay) and 9.1 times (slow decay) as high, respectively, as that a fter DPH alone. The concentrations of DPH distributed into the mucosa of the duodenum and jejunum 1 and 5 h after oral dosing of EDPH were s ignificantly higher than those after DPH alone. The prodrug and DPH co nverted from the prodrug dissolved 2-4 fold more than DPH alone in bil e salt solution and bile salt-oleic acid mixed micelles, indicating th e increased solubility of the prodrug in the intestinal fluid. It is c oncluded from the data that such high solubility of EDPH enhanced the intestinal absorption of the prodrug, part of which would be absorbed in the amide form, and thus gave the high bioavailability.