Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.
Pharmacokinetics and dose-range finding toxicity of a novel anti-HIV active integrase inhibitor.
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新型抗 HIV 活性整合酶抑制剂的药代动力学和剂量范围发现毒性。
DOI：
10.1016/j.antiviral.2014.05.001
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发表时间：
2014
影响因子：
7.6
通讯作者：
Zhong,Yu
中科院分区：
文献类型：
--
作者：
Nair,Vasu;Okello,Maurice;Mishra,Sanjay;Mirsalis,Jon;O'Loughlin,Kathleen;Zhong,Yu
由HIV整合酶催化的病毒DNA整合到人类染色体DNA中代表了HIV感染的“不归路”。因此，HIV整合酶被认为是开发新的抗HIV治疗药物的关键靶点。我们发现了一种新的HIV整合酶抑制剂1，它具有强大的抗病毒活性和良好的代谢特性。本文报道了该化合物的药代动力学和毒代动力学，以及这些发现与进一步开发该整合酶靶向抗病毒药物的相关性。大鼠口服化合物1显示吸收迅速。药物暴露随着药物浓度的增加而增加，表明有适当的剂量依赖关系。化合物1表现出适宜的血浆半衰期、广泛的血管外分布和可接受的生物利用度。毒性研究未发现与化合物相关的临床病理结果。雄性和雌性大鼠红细胞、白细胞和血小板参数均无变化。其他临床化学参数未见与试验品相关的变化。此外，尿中没有检测到胆红素水平，对尿胆红素原或其他尿液分析参数也没有治疗相关的影响。临床前研究还显示，未观察到的不良反应水平和最大耐受剂量都很高（>500 mg/kg/天）。该整合酶抑制剂广泛而显著的抗病毒活性和良好的代谢特征，结合其体内药代动力学和毒性动力学数据及其药理学相关性，为其作为抗hiv治疗剂的进一步发展提供了强有力的关键支持。
Integration of viral DNA into human chromosomal DNA catalyzed by HIV integrase represents the “point of no return” in HIV infection. For this reason, HIV integrase is considered a crucial target in the development of new anti-HIV therapeutic agents. We have discovered a novel HIV integrase inhibitor1, that exhibits potent antiviral activity and a favorable metabolism profile. This paper reports on the pharmacokinetics and toxicokinetics of compound1and the relevance of these findings with respect to further development of this integrase-targeted antiviral agent. Oral administration of compound1in Sprague Dawley rats revealed rapid absorption. Drug exposure increased with increasing drug concentration, indicative of appropriate dose-dependence correlation. Compound1exhibited suitable plasma half-life, extensive extravascular distribution and acceptable bioavailability. Toxicity studies revealed no compound-related clinical pathology findings. There were no changes in erythropoietic, white blood cell or platelet parameters in male and female rats. There was no test-article related change in other clinical chemistry parameters. In addition, there were no detectable levels of bilirubin in the urine and there were no treatment-related effects on urobilinogen or other urinalysis parameters. The preclinical studies also revealed that the no observed adverse effect level and the maximum tolerated dose were both high (>500 mg/kg/day). The broad and significant antiviral activity and favorable metabolism profile of this integrase inhibitor, when combined with thein vivopharmacokinetic and toxicokinetic data and their pharmacological relevance, provide compelling and critical support for its further development as an anti-HIV therapeutic agent.