Pharmacokinetics of Eb and its hydroxypropyl-β-cyclodextrin inclusion complex in rats

Eb及其羟丙基-β-环糊精包合物在大鼠体内的药动学研究(英文)

In our previous study,a novel organic selenium compound Eb was synthesized and found to have significant antitumor activity with much less toxicity compared with the leading compound Ebselen.Unfortunately,Eb was practically insoluble in water （2.57 μg/mL） and had very low oral bioavailability,thus its clinical application was greatly limited.In the present study,the inclusion complex of Eb with 2-hydroxypropyl-β-cyclodextrin （HP-βCD） was prepared and pharmacokinetics of Eb and the inclusion complex were investigated.The water solubility of Eb was dramatically enhanced by inclusion with HP-βCD,which reached 8.4 mg/mL.The pharmacokinetic study showed that the elimination half-life （t 1/2β） of Eb was between 22 h and 30 h and the distribution half-life （t 1/2α） of Eb was 1 h.The results indicated that Eb was rapidly distributed to tissues but slowly eliminated in rats.The absolute bioavailability of Eb/HP-βCD inclusion complex solution through the oral route was 28.3%,and it was 1552% that of Eb in its pure form.In summary,the absorption of Eb in the Eb/HP-βCD inclusion complex was better and faster than that of Eb in its pure form.

在前期研究中我们合成了新型有机硒化合物Eb, 研究发现其比先导化合物Ebselen有更好的抗肿瘤活性和更低的毒性。但Eb几乎不溶于水(2.57 μg/mL)和常见的有机溶剂, 口服生物利用度很低, 限制了其临床应用。在本论文中,我们制备了Eb的HP-βCD包合物, 并研究了Eb及其包合物在大鼠体内的药动学。Eb经包合后其水溶解度显著增加, 达到8.4 mg/mL。药动学研究显示Eb的消除半衰期(t1/2β)在22～30小时间,分布半衰期(t1/2α)约1小时, 纯Eb/HP-βCD包合物溶液的绝对生物利用度是28.3%,是Eb原料的1552%。表明Eb吸收差, 在大鼠体内快速分布, 但缓慢消除, 制成Eb/HP-βCD包合物后显著提高生物利用度。