Kamali F, Ball D E, McLaughlin W S, Seymour R A
Wolfson Unit of Clinical Pharmacology, University of Newcastle, Newcastle Upon Tyne, UK.
J Periodontal Res. 1999 Apr;34(3):145-53. doi: 10.1111/j.1600-0765.1999.tb02235.x.
Interspecies differences in phenytoin (PHT) metabolism to 5-(4-hydroxyphenyl)-5-phenylhydantoin (HPPH) were examined in human, cat and rat hepatic microsomes in vitro. Rat liver microsomes were 25 and 650 times more efficient at the conversion of PHT to HPPH than human and cat liver microsomes, respectively. Sulphaphenazole (83%) and tolbutamide (TOL) (64%) were the most potent inhibitors of HPPH formation in human liver microsomes, while ciprofloxacin (27%), enoxacin (27%) and TOL (26%) produced the greatest inhibition in cat liver microsomes. TOL was tested for its effect on HPPH formation and gingival overgrowth in cats in vivo. Eight cats received PHT sodium (4 mg/kg/d) and another 8 cats received PHT sodium together with TOL (20 mg/kg/d) for 10 wk. Six cats (75%) in the PHT group and 4 cats (50%) in the PHT & TOL group developed significant gingival overgrowth by the end of the study. However, the extent and incidence of the overgrowth were similar in the 2 groups. There were no significant differences in mean AUC 0-10 weeks for plasma PHT (552.90 +/- 29.6 micrograms.d/mL [PHT alone] vs. 582.41 +/- 24.49 micrograms.d/mL [PHT & TOL]) and unconjugated HPPH (1016.4 +/- 295.5 ng.d/mL [PHT alone] vs. 1174.5 +/- 397.2 ng.d/mL [PHT & TOL]) concentrations between the 2 groups of cats. Neither PHT nor HPPH were detectable in the plasma of 8 rats which received PHT (4 mg/kg/d) over a 10-wk period. The rats showed no sign of gingival inflammation (mean gingival index = 0) or gingival overgrowth (mean gingival overgrowth index = 0). Thirty-six adult epileptic patients on chronic PHT therapy were examined; 17 (47%) of the patients demonstrated clinically significant overgrowth. The mean steady-state plasma PHT concentration was comparable to, and the mean plasma unconjugated HPPH concentration 5-fold greater than, that observed in the cats. The results suggest that the rapid metabolism and elimination of PHT and HPPH in the rat may enable it to become more resistant towards developing gingival overgrowth, compared to the cat and man.
在体外对人、猫和大鼠的肝微粒体中苯妥英（PHT）代谢生成5-（4-羟基苯基）-5-苯基乙内酰脲（HPPH）的种间差异进行了研究。大鼠肝微粒体将PHT转化为HPPH的效率分别比人及猫肝微粒体高25倍和650倍。磺胺苯吡唑（83%）和甲苯磺丁脲（TOL）（64%）是人肝微粒体中HPPH生成的最有效抑制剂，而环丙沙星（27%）、依诺沙星（27%）和TOL（26%）在猫肝微粒体中产生的抑制作用最大。对TOL在猫体内对HPPH生成及牙龈过度生长的影响进行了测试。8只猫接受苯妥英钠（4mg/kg/d），另外8只猫接受苯妥英钠加TOL（20mg/kg/d），持续10周。在研究结束时，苯妥英组的6只猫（75%）和苯妥英加TOL组的4只猫（50%）出现了明显的牙龈过度生长。然而，两组中牙龈过度生长的程度和发生率相似。两组猫血浆PHT的平均AUC 0 - 10周（单独使用苯妥英为552.90±29.6微克·天/毫升，苯妥英加TOL为582.41±24.49微克·天/毫升）和未结合的HPPH（单独使用苯妥英为1016.4±295.5纳克·天/毫升，苯妥英加TOL为1174.5±397.2纳克·天/毫升）浓度之间无显著差异。在10周期间接受苯妥英（4mg/kg/d）的8只大鼠的血浆中未检测到PHT和HPPH。这些大鼠没有牙龈炎症迹象（平均牙龈指数 = 0）或牙龈过度生长迹象（平均牙龈过度生长指数 = 0）。对36名接受慢性苯妥英治疗方案的成年癫痫患者进行了检查；其中17名患者（47%）出现了临床上明显的牙龈过度生长。血浆苯妥英的平均稳态浓度与猫相当，血浆未结合的HPPH浓度比猫高5倍。结果表明，与猫和人相比，大鼠体内PHT和HPPH的快速代谢和消除可能使其对牙龈过度生长更具抵抗力。
Zotero 插件