Fujioka H, Tan T, Kishi M, Miyazaki H, Masuda Y, Yokoyama Y
J Pharmacobiodyn. 1986 Mar;9(3):303-14. doi: 10.1248/bpb1978.9.303.
Disposition of 1-benzenesulfonyl-5,5-diphenylhydantoin (II) having a potent anti-inflammatory activity was compared with that of 5,5-diphenylhydantoin (I), an antiepileptic drug, in order to elucidate whether the pharmacodynamic difference between them can be explained by their physicochemical and pharmacokinetic properties. After oral administration of I-14C to rats, radioactivity was distributed in all tissues including the brain, whereas after II-14C administration, the concentrations of radioactivity in most tissues were lower than those in plasma. The results were consistent with the finding obtained by whole-body autoradiography which revealed that after oral administration of II-14C to rats, radioactivity was not transferred into brain but was significantly transferred into inflamed tissues. Brain/plasma concentration ratio of I was about 1.3, whereas that of II was about 0.05. Plasma protein binding of I having pKa value of 8.30 was about 88%, whereas that of II having pKa value of 4.89 was about 99%. The changes in physicochemical properties due to introduction of a benzenesulfonyl group into the hydantoin ring may be responsible for the difference in the disposition between I and II. When II was cerebroventricularly administered to mice, it showed a potent anti-convulsant activity against maximal electroshock seizure, the activity being comparable to that for I. This indicates that the earlier failure to demonstrate the activity of II in a routine screening test for antiepileptic drugs was due to the inability of II to penetrate the blood-brain barrier and to achieve effective concentration in the brain. II was found to inhibit the biosynthesis of prostaglandin. These findings along with the physicochemical properties suggest that although II does not fall structurally under any category of anti-inflammatory drugs the mechanism of action may be similar to that for non-steroidal acidic anti-inflammatory drugs.
为了阐明1-苯磺酰基-5,5-二苯基乙内酰脲（II）（具有强大的抗炎活性）与抗癫痫药物5,5-二苯基乙内酰脲（I）之间的药效学差异是否可以用它们的物理化学和药代动力学性质来解释，对二者的处置情况进行了比较。给大鼠口服I-14C后，放射性分布于包括脑在内的所有组织中，而给予II-14C后，大多数组织中的放射性浓度低于血浆中的浓度。该结果与全身放射自显影的结果一致，全身放射自显影显示给大鼠口服II-14C后，放射性未转移至脑内，但显著转移至炎症组织中。I的脑/血浆浓度比约为1.3，而II的约为0.05。pKa值为8.30的I的血浆蛋白结合率约为88%，而pKa值为4.89的II的血浆蛋白结合率约为99%。由于在乙内酰脲环中引入苯磺酰基而导致的物理化学性质变化可能是I和II在处置上存在差异的原因。当给小鼠脑室内注射II时，它对最大电休克惊厥显示出强大的抗惊厥活性，该活性与I相当。这表明在常规抗癫痫药物筛选试验中未能更早地证明II的活性是由于II无法穿透血脑屏障并在脑内达到有效浓度。发现II可抑制前列腺素的生物合成。这些发现连同其物理化学性质表明，尽管II在结构上不属于任何一类抗炎药物，但其作用机制可能与非甾体酸性抗炎药物的相似。
