Scriba G K, Lambert D M, Poupaert J H
Department of Pharmaceutical Chemistry, School of Pharmacy, University of Münster, Germany.
J Pharm Pharmacol. 1995 Mar;47(3):197-203. doi: 10.1111/j.2042-7158.1995.tb05778.x.
The anticonvulsant activity of phenytoin-lipid conjugates obtained by covalent binding of 3-hydroxy-methylphenytoin to dimyristoylglycerides via a succinidyl linkage, to 2-(1,3-dimyristoylglyceryl)butyric acid and to 3-myristoyl-2-myristoylmethylpropionic acid was evaluated in the maximal electroshock (MES) test and the seizure threshold test with subcutaneous pentetrazol. The phenytoin-lipid conjugates were less active than the parent drug in the MES test after intraperitoneal administration as suspensions, but exhibited comparable activity when injected as a solution in dimethylsulphoxide. They also protected mice from MES-induced seizures following oral administration of aqueous suspensions of the compounds or when incorporated into emulsions. The anticonvulsant activity could be correlated to in-vitro pancreatic lipase-mediated hydrolysis. The bis-deacyl derivatives were at least as active but in some cases also more toxic than phenytoin. Oral administration of two of the lipid conjugates resulted in a faster onset of the anticonvulsant activity compared with the administration of an equimolar dose of phenytoin itself. All compounds were inactive in the subcutaneous pentetrazol test. It is concluded that the lipids act as prodrugs of phenytoin, which is generated by lipolysis upon oral administration.
通过琥珀酰基连接将3-羟甲基苯妥英与二肉豆蔻酰甘油、2-(1,3-二肉豆蔻酰甘油基)丁酸和3-肉豆蔻酰-2-肉豆蔻酰甲基丙酸共价结合得到的苯妥英-脂质缀合物的抗惊厥活性，在最大电休克（MES）试验和皮下注射戊四氮的惊厥阈值试验中进行了评估。苯妥英-脂质缀合物以悬浮液形式腹腔给药后，在MES试验中的活性低于母体药物，但以二甲基亚砜溶液注射时表现出相当的活性。当口服化合物的水悬浮液或将其掺入乳剂中时，它们也能保护小鼠免受MES诱导的惊厥。抗惊厥活性可能与体外胰脂肪酶介导的水解有关。双脱酰基衍生物的活性至少与苯妥英相当，但在某些情况下毒性也比苯妥英更大。与给予等摩尔剂量的苯妥英本身相比，口服两种脂质缀合物导致抗惊厥活性起效更快。所有化合物在皮下注射戊四氮试验中均无活性。结论是脂质作为苯妥英的前药，口服后通过脂解作用产生苯妥英。
