ENHANCEMENT OF ORAL BIOAVAILABILITY OF PHENYTOIN BY ESTERIFICATION, AND IN-VITRO HYDROLYTIC CHARACTERISTICS OF PRODRUGS

To improve the oral absorbability of phenytoin (DPH), prodrugs of DPH with a small acyl substituent, N-carboethoxy- and N-carboisopropoxy-DP H (PT-1 and PT-2, respectively), were synthesized and bioavailabilitie s of them were evaluated after oral administration in rats, compared t o that of DPH dosed. The prodrugs were rapidly hydrolyzed in the intes tinal fluid, intestinal mucosa, liver homogenates and plasma of rats, the plasma giving the highest hydrolytic activity. Two different elimi nations of DPH, slow and rapid, were observed after intravenous and or al administrations of prodrugs. The bioavailabilities of DPH after ora l administration at a dose of 25 mg/kg of PT-1 and PT-2 (DPH equivalen t), increased to approximately 8.5- and 6.0-fold for PT-1 and PT-2 (ra pid elimination group) or 3.0- and 3.0-fold (slow elimination group), respectively, compared to those after dosing of DPH. The plasma levels of DPH converted from PT-2 dosed were lower, but more sustained in sl ow elimination groups than those from PT-1. The normalized AUC values after oral dosing of prodrugs at a dose of 50 mg/kg were increased dra matically, compared to those at a dose of 25 mg/kg, suggesting non-lin ear clearance at a high dose. In order to clarify the mechanism for pr eponderance of intestinal absorption of the prodrugs, concentrations o f parent drug and prodrug were measured in intestinal mucosa after a s ingle oral dosing of 50 mg/kg (DPH equivalent). Upon the administratio n of PT-I and PT-2, greater amounts of DPH, in comparison with those a fter dosing of DPH, and small amounts of intact prodrugs were detected in the duodenal and jejunal mucosa. These data indicated that these p rodrugs was subjected to the extensive intestinal absorption compared to DPH, giving comparatively high plasma levels. Therefore, PT-1 and P T-2 will be useful prodrugs as an orally applicable form. In particula r, PT-2 seems to serve as a benign prodrug with the intention of impro ving the absorption of DPH. (C) 1998 Elsevier Science B.V. All rights reserved.