艾滋病毒1型逆转录酶抑制剂的小鼠血清活性动态研究

作者	单位
彭宗根	中国医学科学院中国协和医科大学医药生物技术研究所病毒室北京 100050
陈鸿珊	中国医学科学院中国协和医科大学医药生物技术研究所病毒室北京 100050
滕立	中国医学科学院中国协和医科大学医药生物技术研究所病毒室北京 100050

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中文摘要:

目的:观察艾滋病毒1型逆转录酶(HIV-1RT)抑制剂在小鼠血清中的活性动态,探讨其在药效评价中的可应用性。方法:不同途径给予小鼠已知和未知HIV-1RT抑制剂后,在不同时间取血分离血清,体外测定血清抑制 HIV-1RT的活性。结果:正常小鼠血清有非特异性抑制HIV-1RT的活性,经稀释后可排除;非核苷类RT抑制剂可在体外直接测定小鼠体内用药后的血清抑制HIV-1RT活性和动态,核苷类RT抑制剂的血清抗HIV-1RT的活性可测出,但血清活性不如非核苷类药物为高,主要因核苷类药物的活性物质是其三磷酸盐,在细胞内转化后形成。此种体外测定小鼠用药后血清活性的体内体外结合的实验方法,简便快速,可初步分析药物与血清蛋白的结合率以及估算其生物利用度和清除率。结论:体内与体外相结合的逆转录酶抑制剂的小鼠血清活性的测定方法,可应用于非核苷类HIV-1RT抑制剂的药效评价,对于核苷类HIV-1RT抑制剂,取血时间要长,并同时测定血清在细胞内的活性,以便综合分析。

英文摘要:

Objective:To observe the dynamics of HIV-1 reverse transcriptase (HIV-1 RT) inhibitor activity in serum of mice, and assess the applicability of the method in evaluating the activity of HIV-1 RT inhibitors. Methods: After mice were treated with HIV-1 RT inhibitors (with known or unknown constituents) through intragastric or intraperitoneal pathways, the activity of HIV-1 RT in serum of mice collected in different times was determined in vitro. Results: Serum of normal mice showed the non-specific inhibition on HIV-1 RT, but it could disappear when the serum was diluted. The inhibitory effects of HIV-1 RT in mice serum collected after given non-nucleotide reverse transcriptase inhibitors (NNRTIs) oould be well and immediately determined. But that in serum collected after given nucleotide reverse transcriptase inhibitors (NRTIs) was weak, because this kind of RT inhibitor could display the inhibition on HIV-1 RT only when it has been activated through phosphorylation in the cells and acts as competitive inhibitors. The degree of binding between drug and albumin, the bioactivity and the clearance rate of drugs can also be analyzed by this method. Conclusion: The in vitro and in vivo combined method for detection of RT inhibitor activity in mice serum could be applied in quick drug effect evaluation of HIV-1 NNRTIs. But as it is applied to determine the RT inhibitory activity of NRTIs, the blood collecting time should be delayed and the activity should be determined both in vitro and in vivo parallelly for a comprehensive analysis.

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