PHARMACOKINETIC ANALYSIS OF PHENYTOIN AND ITS DERIVATIVES IN PLASMA AND BRAIN IN RATS

The derivatives of phenytoin (DPH) were synthesized by the reaction at 3 position of hydantoin ring with valproic acid and valeric acid, pro ducing valproyl DPH (VPDPH) and valeroyl DPH (VADPH), respectively. Th ese derivatives showed much higher lipid solubilities than that of DPH . Their distribution and elimination were compared to those of DPH. Ad ditionally, the concentration profiles of the drugs in brain and plasm a were analyzed with a modified 2-compartment model. DPH and its deriv atives, without hydrolysis to DPH in blood, were found rapidly distrib uted into brain, although the distribution of derivatives was much les s, probably due to the high protein binding capacities. The distributi on of DPH and its derivatives into brain regions was similar to that i nto the cortex cerebri. VPDPH and VADPH were more rapidly eliminated f rom plasma and brain than DPH, giving smaller mean residence time (MRT ) values (0.92 and 0.85 h) and much smaller cortex/plasma concentratio n ratio than those of DPH. The VPDPH and VADPH concentrations in the c erebrospinal fluid (CSF) were also much lower than that of DPH. The ti me course of plasma and brain concentrations of DPH and its derivative s after i.v. administration was successfully described by the modified 2-compartment models presented.