EVALUATION OF VALPROIC ACID (VPA) DEVELOPMENTAL TOXICITY AND PHARMACOKINETICS IN SPRAGUE-DAWLEY RATS
EVALUATION OF VALPROIC ACID (VPA) DEVELOPMENTAL TOXICITY AND PHARMACOKINETICS IN SPRAGUE-DAWLEY RATS
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DOI：
10.1016/0272-0590(88)90112-1
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发表时间：
1988-10-01
期刊：
影响因子：
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通讯作者：
HENDRICKX, AG
中科院分区：
文献类型：
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作者：
BINKERD, PE;ROWLAND, JM;HENDRICKX, AG
本研究旨在评估抗惊厥药丙戊酸（VPA）（一种人类致畸剂）在Sprague-Dawley大鼠中的药代动力学和发育毒性。口服给予200-800 mg/kg VPA（5-20 × 105），人治疗剂量），导致在较高剂量下母体毒性增加，在800 mg/kg下100%母体致死率。尽管在600 mg/kg剂量下吸收发生率增加（48 ± 0.5%），43%）相比，对照组（18 .+-. 24%），无统计学意义。GD 20的胎仔检查显示剂量依赖性胎仔生长迟缓（≤0.05），除了中轴骨和外骨骼骨化不全外，胎儿体重和身长也降低。骨骼缺陷的发生率，包括异常椎骨、肋骨和颅面畸形，也随着VPA剂量的增加而增加。在两个最高剂量治疗组中观察到的心脏异常包括大血管畸形伴或不伴相关室间隔缺损（VSD）。在600 mg/kg组中还观察到泌尿生殖系统缺陷。GD 8时的血浆消除半衰期为1.0 ±。0.3 200 mg/kg和2.3 . ±.小时。0.7 h，600 mg/kg。总药物和游离药物的最大浓度为341 . ±. 18 μ g/ml和181 ±. 11 μ g/ml，低剂量组和911 . ±. 379 μ g/ml和542 ±.高剂量组为224 μ g/ml。在10天治疗期间，在任一剂量水平下均未观察到任何药代动力学参数（t1/2、AUC、Cmax、tmax）的显著变化。
This study was undertaken to assess the pharmacokinetics and developmental toxicity of the anticonvulsant, valproic acid (VPA), a human teratogen, in Sprague-Dawley rats. Oral administration of 200-800 mg/kg VPA (5-20 .times. human therapeutic dose) from Gestational Days (GD) 8 to 17 resulted in increasing maternal toxicity at the higher doses with 100% maternal lethality at 800 mg/kg. Although there was an increased incidence of resorptions at 600 mg/kg (48 .+-. 43%) compared to controls (18 .+-. 24%), it was not statistically significant. Fetal examination on GD 20 revealed dose-dependent fetal growth retardation (.ltoreq. 0.05) as evidenced by decreased fetal weight and length in addition to underossification of both the axial and appendicular skeleton. The incidence of skeletal defects, including abnormal vertebrae, ribs, and craniofacial dysmorphia, also increased with higher doses of VPA. Cardiac anomalies observed in the two highest treatment groups consisted of great vessel malformations with or without associated ventricular septal defects (VSDs). Urogenital defects were also noted in the 600 mg/kg group. The plasma elimination half-life on GD 8 was 1.0 .+-. 0.3 hr at 200 mg/kg and 2.3 .+-. 0.7 hr at 600 mg/kg. Maximal concentrations of total and free drug were 341 .+-. 18 .mu.g/ml and 181 .+-. 11 .mu.g/ml, respectively, in the low-dose group and 911 .+-. 379 .mu.g/ml and 542 .+-. 224 .mu.g/ml in the high-dose group. No significant changes in any pharmacokinetic parameters (t 1/2, AUC, Cmax, tmax) were observed over the 10-day treatment period at either dose level.