Improved Anticonvulsant Activity of Phenytoin by a Redox Brain Delivery System II: Stability in Buffers and Biological Materials

Abstract

The stability of nine chemical delivery systems (CDSs) for phenytoin (DPH) was studied in aqueous buffers and in biological materials. The systems were based on a dihydropyridine ⇔ quaternary pyridinium salt redox pair attached to 3-(hydroxymethyl)phenytoin via an ester linkage. The pyridinium derivatives released DPH in aqueous buffers and their hydrolytic reactivity was consistent with their chemical structure. Although in rat blood and plasma all pyridinium esters hydrolyzed rapidly, there was a wide range in the hydrolysis rates in rat brain homogenate. The sterically hindered 1-alkylcarboxynicotinamide was the least reactive ester (t1/2 = 98.2 min), while the trigonellylglycolate ester was the fastest to hydrolyze enzymatically (t1/2 = 2 min) in rat brain homogenate. In acidic media, the major products of all dihydropyridine esters were the corresponding water adducts, the 6-hydroxy-1,4,5,6-tetrahydropyridines. These adducts were of no significance in biological materials. After comparison of the relative stability of the corresponding pairs of dihydropyridine and pyridinium ion in brain homogenate and the absolute stability of the various dihydropyridines, two CDSs were chosen for further in vivo evaluations. The CDSs chosen were the dihydrotrigonellinate ester and its 6-methyl derivative.