苯妥英锌对小鼠大鼠和家兔的毒性

Studies on the toxicity of Phenytoin Zinc

目的本文对苯妥英锌 (PZ)的急性毒性、刺激性、亚急性毒性、蓄积毒性以及大鼠长期服用后体内锌 (Zn)、铜 (Cu)浓度的变化进行研究。方法PZ小鼠灌胃计算LD50 ;兔眼结膜法考察PZ溶液的刺激性 ;大鼠长期分别服用PZ或苯妥英钠 (PS) 2 5周 (剂量分别为 :6 0mg·kg-1·d-1和 2 0mg·kg-1·d-1) ,尾静脉取血 ,测定血清中血红蛋白量 (Hb)、血小板数 (PT)、白细胞总数(WBC)和血清谷丙转氨酶活力 (SGPT) ;用高效液相色谱法监测血中苯妥英 (PHT)浓度 ;服药结束后大鼠断头处死 ,立即取出心脏、肝脏、肾脏和全脑 ,称重 ,计算脏器重量指数 (VWP) ,光镜下对心脏、肝脏、肾脏利全脑进行组织学检查 ,并用原子吸收分光光度法测定血清、肝脏、海马和小脑中Zn和Cu的浓度。结果PZ小鼠灌胃后的LD50 为 14 1.2± 10 .5mg·kg-1,与PS相近 ;PZ溶液的刺激性比PS小 ;大鼠长期服药后 ,仅PS高剂量组使Hb量和PT数明显下降 ,药物对WBC总数和SGPT活力无影响 ;服药期间两药血清中PHT的浓度与剂量成正比 ,低剂量时为 2 3.0 2± 10 .7μmol·L-1,高剂量时为 6 9.4 4± 12 .7μmol·L-1;PZ组全脑的VWP比对照组偏高 ,而PS组比对照组偏低 ;光镜下可见细胞结构清楚 ,无明显组织学改变 ;PS组使肝脏Zn浓度降低了2 5 % ,血清和海马Zn浓度增高了 4

Objective To investigate the toxicity of phenytoin zinc (PZ), including the acute toxicity, irritation, subacute toxicity, cumulative toxicity and concentration alteration of Zn and Cu as well. Methods The mice were oral administrated with PZ to calculate the LD 50; The irritation of PZ solution was explored by rabbit conjunctival of eye; The rats were taken PZ or phenytoin sodium (PS) orally for 25 weeks (doses: 60 mg·kg -1· d -1 and 20 mg·kg -1· d -1). The blood were sampling from tail vein to assay the serum hemoglobin (Hb), platelet (PT), white blood cell (WBC) and glutamic-pyruvic transaminase (SGPT); The serum PHT level was monitored by high performance liquid chromatography; The rats were put to death by decapitation immediately after administration, the heart, liver, kidney and whole brain were weighed to calculate the viscera weight percentage (VWP) and checked by optical microscope for histological alteration; The levels of Zn and Cu in serum, liver, hippocampus and cerebellum were detected by atomic absorption spectrophotometry. Results The LD 50 of PZ was 141.2± 10.5mg·kg -1, which is comparable with PS; The irritation of PZ was less than PS: after long-term administration to rats, Hb and PT were significantly decreased only in High-dose group, however, WBC and SGPT were unchanged. The PHT concentration in serum showed dose-dependent tendency of both PZ and PS during administration, which is 23.02±10.7 μmol· L -1 in low-dose group and 69.44 ± 12.7 μ mol· L -1 in high-dose group. The VWP of whole brain in PZ group was increased compared with control group, which in PS group was decreased. No obvious damage was observed in optical microscope. PS group reduced Zn level in liver by 25%, and increased in serum and hippocampus by 43% and 17%, nevertheless, PZ group increased Zn level in liver by 47% and reduced in serum by 27%. Cu level of viscera was almost unchanged. Conclusion The irritation and subacute toxicity of PZ were both less than PS, acute toxicity was comparable to PS, and PZ have no Zn accumulated toxicity in organism. PZ could increase Zn concentration in the liver and decrease it in the serum, but didn't change it in the brain, thus diminished the toxicity of PHT by cerebellar dysfunction and degeneration.