EFFECTS OF PHENYTOIN ON THE IN-VIVO KINETICS OF THIAMINE AND ITS PHOSPHOESTERS IN RAT NERVOUS TISSUES

The in vivo effects of chronic (30 days) and subchronic (10 days) intr agastric treatment with phenytoin (PHT) (500 mg/kg) b.wt., suspended i n 10% arabic gum water solution) on the uptake and metabolism of thiam ine (T), T monophosphate (TMP) and T pyrophosphate (TPP) were evaluate d in rat nervous regions (cerebral cortex, brainstem, cerebellum and s ciatic nerve) by determining the radioactivity of T and its phosphoest ers in plasma and tissues at fixed time intervals (0.25-240 h) after a n i.p. injection of thiazole-[2-C-14]thiamine (30 mug: 1.25 muCi). A n utritionally adequate diet containing T in excess was given to the ani mals in order to produce a virtually stable content of T compounds in the tissues. Analytical data were processed by using a compartmental m odel which allowed the calculation of fractional rate constants (FRC), turnover rates (TR) and turnover times. Compared with vehicle-treated controls, animals treated chronically with PHT exhibited lower levels of radiolabelled T compounds in all nervous regions except for the ce rebral cortex. These alterations were not found in animals receiving s ubchronic treatment. Evaluation of FRC values indicated that PHT-induc ed effects on T metabolism differed depending on the length of PHT tre atment and the nervous region considered. Overall, PHT appeared to int erfere mainly with T and TMP uptake, TPP dephosphorylation to TMP and TPP turnover times, these effects being particularly prominent in the cerebellum and in the brainstem of chronically treated animals. Since all changes in T uptake and metabolism were observed in the absence of overt behavioural toxicity, these findings may have potential clinica l relevance in highlighting possible mechanisms by which PHT therapy c an alter brain metabolism.