In vivo kinetic analysis of covalent binding between N-acetyl-L-cysteine and plasma protein through the formation of mixed disulfide in rats
In vivo kinetic analysis of covalent binding between N-acetyl-L-cysteine and plasma protein through the formation of mixed disulfide in rats
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DOI：
10.1023/a:1015349928000
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发表时间：
2002-05-01
影响因子：
3.7
通讯作者：
Otagiri, M
中科院分区：
文献类型：
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作者：
Harada, D;Naito, S;Otagiri, M
目的。本研究旨在探讨血浆药物清除率与n-乙酰- l-半胱氨酸（NAC）共价蛋白结合动力学的关系。NAC经大鼠静脉注射或连续输注。考虑蛋白结合过程，采用室室模型分析血浆中未结合蛋白和总NAC的浓度，得到表观一级结合速率常数k(o)n和k(o)ff。大剂量注射后血浆总NAC呈双相消除，并在1小时出现拐点。1小时后，NAC主要以共价蛋白结合形式存在。在输注的稳定状态下，大约30%-40%的血浆NAC与蛋白质共价结合。k(o)n、k(o)ff和蛋白非结合药物的消除速率常数k(e)分别为0.23、0.57和4.3 hr（-1）。由k(o)ff估计的NAC与蛋白质的解离半衰期与血浆总NAC的消除半衰期一致。这表明NAC与蛋白质的分离率限制了血浆中药物的消除(k（o)ff < k(e)）。我们证明血浆总药物清除率受到共价蛋白结合的动力学限制。这里描述的室室模型对分析其体内动力学是有用的。
Purpose. This investigation was undertaken to study the relationship between plasma drug clearance and covalent protein-binding kinetics of N-acetyl-L-cysteine (NAC).Methods. NAC was intravenously administered to rats via a bolus injection or continuous infusion. Plasma concentrations of protein-unbound and total NAC were analyzed using a compartment model, taking into consideration of the protein binding process, and the apparent first-order binding and dissociation rate constants (k(o)n and k(o)ff) were obtained.Results. Plasma total NAC after a bolus injection showed biphasic elimination with an inflection point at 1 hr. After 1 hr, NAC was largely present in the covalent protein-bound form. During the steady state of the infusion, approximately 30%-40% of plasma NAC bound with protein covalently. The k(o)n, k(o)ff, and the elimination rate constant of protein-unbound drug (k(e)) were 0.23, 0.57, and 4.3 hr(-1). The dissociation half-life of NAC from protein estimated from k(o)ff was in agreement with the elimination half-life of plasma total NAC. This suggests that the dissociation of NAC from protein rate-limited the drug elimination in plasma (k(o)ff < k(e)).Conclusion. We demonstrated that plasma total drug clearance is kinetically limited by covalent protein binding. The compartmental model described here is useful for analyzing its kinetics in vivo.