PHYSICOCHEMICAL AND HYDROLYTIC CHARACTERISTICS OF PHENYTOIN DERIVATIVES

To further clarify the pharmacokinetic characteristics of phenytoin (D PH) and its derivatives, DPH-1-methylnicotininate (MNDPH), valeroyl DP H (VADPH) and valproyl DPH (VPDPH), in plasma and brain, we have inves tigated their physicochemical properties and protein binding character istics. Additionally, the hydrolytic conversion of these derivatives t o DPH was also studied using small intestine, liver and brain tissues, as well as rat plasma. The log partition coefficient (PC) values of a ll derivatives were much higher than that of DPH. Judging from their p K(a) values (5.68 and 5.91 for VADPH and VPDPH, respectively) and pH-s olubilities, VADPH and VPDPH were acidic compounds, while MNDPH was ba sic. These data indicated that most fractions of VADPH and VPDPH exist ed as an ionized form (these fractions existed in an ionized form, 0.9 8 and 0.97, respectively) at physiological pH, whereas MNDPH existed a s a unionized form under the same conditions. Rosenthal or Scatchard p lots of the binding data of DPH and its derivatives to both rat plasma protein and bovine serum albumin (BSA) exhibited straight lines over their concentration ranges used, indicating that DPH and its derivativ es have a single binding site on the protein. The binding potencies (K or n.P-1 value) of the derivatives to both proteins were much greater than that of DPH. No DPH produced from VADPH and VPDPH was found in t he biological fluids over a period of 24h. However, the hydrolysis of MNDPH to DPH was observed in plasma and the tissues used, with the mos t rapid hydrolysis in the small intestine, and the hydrolysis rate con stant in plasma was ca. 20-fold greater than that in the brain. The pr esent results lead us to propose that the low uptake of VADPH and VPDP H into the brain, as well as their rapid elimination from plasma is ma inly ascribed to both the high protein binding and the large dissociat ion of derivatives in the plasma, compared with that of DPH.