Ramanathan M
Department of Pharmaceutics, State University of New York at Buffalo 14260-1200, USA.
Cytokine. 1997 Jan;9(1):19-26. doi: 10.1006/cyto.1996.0131.
Soluble receptors (sr) can both inhibit and stimulate cytokine bioactivity. The extent to which sr stabilizes the loss of cytokine bioactivity is an important determinant of whether a sr exerts an agonist-like or antagonist-like pharmacological effect. However, the half-life of sr-bound cytokines can be difficult to determine experimentally because methods that disrupt the sr-cytokine complex can cause loss of cytokine bioactivity. The purpose of this study was to test whether a parsimonious pharmacokinetic model in which the sr stabilizes the decay of short-lived cytokines can be used to determine the half-life of tumour necrosis factor-alpha (TNF-alpha) bound to two human urine-derived sr. A mathematical model which assumes cytokine-sr equilibrium, constant total sr concentration and first-order kinetics for loss of cytokine bioactivity was used. In addition, the model assumes that the experimentally observed bioactivity is related to the free cytokine concentration. The authors fitted experimental data reported by Aderka et al. for two TNF-alpha sr [Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D (1992) J Exp Med 175:323-329] and estimated the half-life of sr-bound TNF-alpha. The parameter estimates were plausible and comparable to those obtained by other methods and, additionally, the model predicted the unexpected relationship between sr dose and cytokine-free concentration that is observed after 9 days of TNF-alpha exposure.
可溶性受体（sr）既能抑制也能刺激细胞因子的生物活性。sr稳定细胞因子生物活性丧失的程度是其发挥激动剂样或拮抗剂样药理作用的一个重要决定因素。然而，与sr结合的细胞因子的半衰期可能很难通过实验确定，因为破坏sr - 细胞因子复合物的方法可能会导致细胞因子生物活性丧失。本研究的目的是测试一个简约的药代动力学模型，其中sr稳定短寿命细胞因子的衰变，是否可用于确定与两种人尿源性sr结合的肿瘤坏死因子-α（TNF-α）的半衰期。使用了一个数学模型，该模型假定细胞因子 - sr平衡、总sr浓度恒定以及细胞因子生物活性丧失的一级动力学。此外，该模型假定实验观察到的生物活性与游离细胞因子浓度相关。作者拟合了Aderka等人报告的两种TNF-α sr的实验数据[Aderka D, Engelmann H, Maor Y, Brakebusch C, Wallach D (1992) J Exp Med 175:323 - 329]，并估计了与sr结合的TNF-α的半衰期。参数估计是合理的，并且与通过其他方法获得的估计值相当，此外，该模型预测了在TNF-α暴露9天后观察到的sr剂量与无细胞因子浓度之间的意外关系。
