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
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DOI：
10.1111/j.1745-7254.2005.00163.x
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发表时间：
2005-10-01
影响因子：
8.2
通讯作者：
Liang, Q
中科院分区：
文献类型：
--
作者：
Dai, SJ;Dou, GF;Liang, Q
目标：研究新型抗人类免疫缺陷病毒（HIV）多肽西夫韦肽在猴体内的药代动力学，比较西夫韦肽和恩夫韦肽对HIV-1感染细胞融合的抑制浓度。方法：猴iv或sc西夫韦肽1.2mg/kg。建立了在线固相萃取-液相色谱-串联质谱法（SPELC/MS/MS）测定猴血浆中西夫韦肽的浓度。使用4-I-127碘化肽作为内标。通过共培养试验测定西夫韦肽对细胞融合的50%抑制浓度（IC 50）。结果：该方法具有良好的精密度和准确度。血浆中西夫韦肽的校准曲线在4.88-5000 μ g/L范围内呈线性，相关系数大于0.9923。iv或sc给药后，观察到的西夫韦肽峰浓度分别为10626 +/- 2886 μ g/L和528 +/- 191 μ g/L，终末消除半衰期（T，12）分别为6.3 +/- 0.9 h和5.5 +/- 1.0 h。皮下给药后，Tmax为0.25-2 h，绝对生物利用度为49% ± 13%。西夫韦肽抑制HIV-1慢性感染细胞和未感染细胞之间的合胞体形成，IC 50为0.33 μ g/L。结论：建立了在线SPE-LC/MS/MS方法用于多肽药代动力学研究。西夫韦肽经皮下迅速吸收进入血液循环。西夫韦肽的T-1/2明显长于其类似物恩夫韦肽，在健康猴中报告，并且其长期血浆浓度水平高于其体外IC 50。
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.