Ladjimi H, Gounelle J C
Faculté de Sciences Pharmaceutiques et Biologiques, Laboratoire de Physiologie, Châtenay-Malabry, France.
Arch Int Physiol Biochim Biophys. 1994 May-Jun;102(3):189-93. doi: 10.3109/13813459409007536.
To further define the mechanism of interaction among phenytoin, folates and cobalamins in rats, we studied the effect of phenytoin (60 mg/(kg.day)) with or without folic acid supplementation and with or without cobalamin deficiency, as well as the effect of supplementing with folic acid (200 mg/kg diet) with or without a cobalamin deficiency, on the tissue concentrations of folates and phenytoin (determined respectively by HPLC and fluorescence polarization). The major tissues (liver, intestinal mucosae, blood and brain) were studied. A folic acid overload (estimated at about 2 mg/day) increased folate levels in the liver, the intestinal mucosae and blood, while there was no effect on cerebral levels. Phenytoin had no significant effect on folate tissue concentration. The major finding was that a folic acid overload caused a considerable decrease in the hepatic and cerebral concentrations of phenytoin. This decrease could be responsible for the increased frequency of epileptic fits in patients treated with this anticonvulsant drug when combined with a folic acid supplement. Concentration changes of the drug in cobalamin-replete or -deficient rats, with or without folic acid supplementation, suggest that the interaction between the anticonvulsant and the two vitamins (folates and cobalamins) occurs at the level of transmethylation reactions.
为了进一步明确苯妥英钠、叶酸和钴胺素在大鼠体内的相互作用机制，我们研究了苯妥英钠（60毫克/（千克·天））在补充或不补充叶酸以及钴胺素缺乏或不缺乏的情况下的作用，以及补充叶酸（200毫克/千克饲料）在钴胺素缺乏或不缺乏的情况下对叶酸和苯妥英钠组织浓度的影响（分别通过高效液相色谱法和荧光偏振法测定）。我们研究了主要组织（肝脏、肠黏膜、血液和大脑）。叶酸过量（估计约为2毫克/天）会增加肝脏、肠黏膜和血液中的叶酸水平，但对大脑中的叶酸水平没有影响。苯妥英钠对叶酸组织浓度没有显著影响。主要发现是，叶酸过量会导致肝脏和大脑中苯妥英钠的浓度大幅降低。这种降低可能是使用这种抗惊厥药物并补充叶酸的患者癫痫发作频率增加的原因。在补充或不补充叶酸的钴胺素充足或缺乏的大鼠中，药物浓度的变化表明，抗惊厥药物与两种维生素（叶酸和钴胺素）之间的相互作用发生在转甲基反应水平。
