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首页> 外文期刊>Drug and Chemical Toxicology >Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs
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Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs

机译：新型化学预防剂SHetA2在大鼠和狗中的口服毒性和药代动力学研究

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摘要

SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1 %) systemic bioavailability of SHetA2 for all doses tested.The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level.The no observed adverse effect level (NOAEL) was 500 mg/kg/ day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol~R HS 15 was observed in any tested dose groups (0,100,400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.
机译：SHetA2是一种杂芳烃类化合物，在不激活视黄酸受体的情况下，具有选择性抑制癌细胞生长和诱导细胞凋亡的作用。在大鼠研究中，SHetA2以1％甲基纤维素水溶液/0.2% Tween 80口服灌胃，分别在0、100、500和2,000 mg / kg / day的情况下给药28天。高剂量给药导致雄性大鼠活动减少，体重增加和食物消耗减少以及器官重量变化。大鼠血浆中SHetA2的主要代谢产物是单羟基SHetA2，在口服和静脉内给药后，其含量明显高于母体化合物。药代动力学分析显示，在所有测试剂量下，SHetA2的全身生物利用度极低（<1％）。2,000 mg / kg /天的剂量被认为是最低的观察到的不良反应水平，未观察到的不良反应水平（NOAEL）为500 mg /公斤/天。在狗研究中，在任何测试剂量组（0,100,400和1,500 mg / kg /天）中，均未观察到SHetA2在30％Solutol〜R HS 15水溶液中的毒性。狗血浆中SHetA2的主要代谢产物也是单羟基SHetA2，其在口服后等于或低于母体化合物。与大鼠血浆相比，狗血浆中的SHetA2水平明显更高。但是，暴露与剂量不成正比，例如，随着剂量的增加，血浆浓度-时间曲线下最大浓度或面积缺乏成比例的增加。未确定NOAEL，并且被认为高于1,500 mg / kg /天。

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