Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro

	Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro
	Dai SJ 2; Dou GF 3; Qian XH5; Song HF; Tang ZM 2; Liu DS 2; Liu XW 2; Yang LM 6; Zheng YT 6; Liang Q 7; qianxh@nic.bmi.ac.cn ; songhf@nic.bmi.ac.cn
	2005
发表期刊	ACTA PHARMACOLOGICA SINICA
ISSN	1671-4083
卷号	26 期号:10 页码:1274-1280
合作性质	其它
摘要	Aim: To study the pharmacokinetics of sifuvirtide, a novel anti-human immunodeficiency virus (HIV) peptide, in monkeys and to compare the inhibitory concentrations of sifuvirtide and enfuvirtide on HIV-1-infected-cell fusion. Methods: Monkeys received 1.2 mg/kg iv or sc of sifuvirtide. An on-line solid-phase extraction procedure combined with liquid chromatography tandem mass spectrometry (SPELC/MS/MS) was established and applied to determine the concentration of sifuvirtide in monkey plasma. A four-I-127 iodinated peptide was used as an internal standard. Fifty percent inhibitory concentration (IC50) of sifuvirtide on cell fusion was determined by co-cultivation assay. Results: The assay was validated with good precision and accuracy. The calibration curve for sifuvirtide in plasma was linear over a range of 4.88-5000 mu g/L, with correlation coefficients above 0.9923. After iv or sc administration, the observed peak concentrations of sifuvirtide were 10626 +/- 2886 mu g/L and 528 +/- 191 mu g/L, and the terminal elimination half-lives (T,12) were 6.3 +/- 0.9 h and 5.5 +/- 1.0 h, respectively. After sc, T-max was 0.25-2 h, and the absolute bioavailability was 49% +/- 13%. Sifuvirtide inhibited the syncytium formation between HIV-1 chronically infected cells and uninfected cells with an IC50 of 0.33 mu g/L. Conclusion: An on-line SPE-LC/MS/MS approach was established for peptide pharmacokinetic studies. Sifuvirtide was rapidly absorbed subcutaneously into the blood circulation. The T-1/2 of sifuvirtide was remarkably longer than that of its analog, enfuvirtide, reported in healthy monkeys and it conferred a long-term plasma concentration level which was higher than its IC50 in vitro.
关键词	Sifuvirtide Hiv Fusion Inhibitors Pharmacokinetics Hiv Enfuvirtide On-line Solid-phase Extraction Macaque
资助者	Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the Na- tional High Technology Research and Deve- lopment Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004- BA719A14), and Key Scientific and Techno- logical Projects of Yunnan (No 2004NG12). ; Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the Na- tional High Technology Research and Deve- lopment Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004- BA719A14), and Key Scientific and Techno- logical Projects of Yunnan (No 2004NG12). ; Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the Na- tional High Technology Research and Deve- lopment Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004- BA719A14), and Key Scientific and Techno- logical Projects of Yunnan (No 2004NG12). ; Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the Na- tional High Technology Research and Deve- lopment Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004- BA719A14), and Key Scientific and Techno- logical Projects of Yunnan (No 2004NG12).
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收录类别	SCI
语种	英语
资助者	Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the Na- tional High Technology Research and Deve- lopment Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004- BA719A14), and Key Scientific and Techno- logical Projects of Yunnan (No 2004NG12). ; Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the Na- tional High Technology Research and Deve- lopment Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004- BA719A14), and Key Scientific and Techno- logical Projects of Yunnan (No 2004NG12). ; Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the Na- tional High Technology Research and Deve- lopment Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004- BA719A14), and Key Scientific and Techno- logical Projects of Yunnan (No 2004NG12). ; Project supported by the National Natural Science Foundation of China (No 39930180, 20275046, 30321003, 30371669), the Na- tional High Technology Research and Deve- lopment Program (No 2003AA2Z347B, 2002BA711A11, 2004BA711A18, 2004- BA719A14), and Key Scientific and Techno- logical Projects of Yunnan (No 2004NG12).
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/4537
专题	科研部门_分子免疫药理学（郑永唐）
通讯作者	qianxh@nic.bmi.ac.cn; songhf@nic.bmi.ac.cn
作者单位	1.* 2.Laboratory of Metabolism of Biotechnology Derived Drugs, Beijing Institute of Radiation Medicine, Beijing 100850 3.Laboratory of Drug Metabolism and Pharmacokinetics, Beijing Institute of Transfusion Medicine, Beijing 100850 4.* 5.Laboratories of Genomics and Proteomics, Beijing Institute of Radiation Medicine, Beijing 100850 6.Laboratory of Molecular Immunopharmacology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223 7.FusoGen Pharmaceuticals Inc, Tianjin 300051, China
推荐引用方式 GB/T 7714	Dai SJ,Dou GF,Qian XH*,et al. Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro[J]. ACTA PHARMACOLOGICA SINICA,2005,26(10):1274-1280.
APA	Dai SJ.,Dou GF.,Qian XH.,Song HF.,Tang ZM.,...&songhf@nic.bmi.ac.cn.(2005).Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro.ACTA PHARMACOLOGICA SINICA,26(10),1274-1280.
MLA	Dai SJ,et al."Pharmacokinetics of sifuvirtide, a novel anti-HIV-1 peptide, in monkeys and its inhibitory concentration in vitro".ACTA PHARMACOLOGICA SINICA 26.10(2005):1274-1280.

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