Stella V J, Martodihardjo S, Rao V M
Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA.
J Pharm Sci. 1999 Aug;88(8):775-9. doi: 10.1021/js980489i.
Some physicochemical properties of N-acyloxyalkyl prodrugs of phenytoin were reported previously.(1,2) It was shown that despite their lower aqueous solubilities relative to phenytoin, these lower-melting prodrugs with apparently disrupted crystalline structures gave either comparable or enhanced in vitro solubility and dissolution rate in simulated intestinal media made up of bile salts and lecithin (SIBLM).(2) The current objective was to compare the in vivo behavior of two of these prodrugs to phenytoin in dogs and attempt to correlate the in vitro behavior to their in vivo behavior. The oral bioavailability of phenytoin after administration of phenytoin (1) and the selected prodrugs, 3-pentanoyloxymethyl 5, 5-diphenylhydantoin (2) and 3-octanoyloxymethyl 5, 5-diphenylhydantoin (3), in fed and fasted beagle dogs were compared to intravenously administered phenytoin. Phenytoin and its prodrugs showed improvement in fed-state phenytoin bioavailability relative to the fasted state indicating that food enhanced the delivery of phenytoin from phenytoin and its prodrugs. The increased bioavailability in the fed state may be due to stimulation of bile release by food and, for the prodrugs, possible catalysis of their dissolution by lipases.(3) In both, fasted and fed states, prodrugs 2 and 3 gave higher AUC values of phenytoin than the parent compound. The enhanced bioavailability of phenytoin after oral administration were more obvious in fed dogs. Although enhanced, AUC values of phenytoin from the prodrugs relative to phenytoin were not statistically different (at 95% confidence level) in fasted state, but were different in fed state. Although the aqueous solubilities and dissolution of both prodrugs were lower than phenytoin, dissolution of 2 and 3 was equivalent and greater, respectively, relative to phenytoin in SIBLM. As expected, the in vivo behavior correlated better with the in vitro SIBLM dissolution behavior. These results indicate that aqueous solubility per se does not adequately predict in vivo behavior.
先前已报道了苯妥英N - 酰氧基烷基前药的一些物理化学性质。(1,2)结果表明，尽管这些前药相对于苯妥英的水溶性较低，但这些具有明显破坏晶体结构的低熔点前药在由胆盐和卵磷脂组成的模拟肠道介质（SIBLM）中具有相当或更高的体外溶解度和溶解速率。(2)当前的目标是比较其中两种前药与苯妥英在犬体内的行为，并尝试将体外行为与其体内行为相关联。在喂食和禁食的比格犬中，比较了给予苯妥英（1）以及选定的前药3 - 戊酰氧基甲基5,5 - 二苯基乙内酰脲（2）和3 - 辛酰氧基甲基5,5 - 二苯基乙内酰脲（3）后苯妥英的口服生物利用度，并与静脉注射苯妥英进行比较。相对于禁食状态，苯妥英及其前药在喂食状态下的苯妥英生物利用度有所提高，这表明食物增强了苯妥英及其前药中苯妥英的递送。喂食状态下生物利用度的增加可能是由于食物刺激胆汁释放，对于前药而言，可能是脂肪酶催化其溶解。(3)在禁食和喂食状态下，前药2和3产生的苯妥英AUC值均高于母体化合物。苯妥英口服给药后生物利用度的提高在喂食犬中更为明显。尽管有所提高，但前药中苯妥英的AUC值相对于苯妥英在禁食状态下无统计学差异（95%置信水平），但在喂食状态下存在差异。尽管两种前药的水溶性和溶解速率均低于苯妥英，但在SIBLM中，前药2和3的溶解分别与苯妥英相当且更高。正如预期的那样，体内行为与体外SIBLM溶解行为的相关性更好。这些结果表明，水溶性本身并不能充分预测体内行为。
