Levitt David G, Levitt Michael D
Department of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN 55455, USA;
Medicine Service, Veterans Affairs Medical Center, Minneapolis, MN. 55417, USA;
ADMET DMPK. 2023 Jan 26;11(1):57-80. doi: 10.5599/admet.1570. eCollection 2023.
Increased plasma concentrations of a variety of cellular enzymes (alanine transaminase, aspartate aminotransferase, alkaline phosphatase, amylase, etc.) are commonly used as routine screening tests for a range of conditions. An increased concentration usually is assumed to result from an increased rate of delivery to the plasma. Factors such as decreased metabolism or excretion or altered extravascular distribution usually are ignored. As a prelude to a detailed analysis of all the factors producing altered plasma enzyme levels, we have reviewed the relevant literature describing the pharmacokinetics (PK) of 13 of the commonly measured plasma proteins and developed a PK model that provides a simple physiological description of all the data. Our model starts with the general 3-compartment, 6-parameter system previously developed for albumin and interprets the fluxes in terms of unidirectional sieved protein convectional volume flows from the plasma to the two tissue compartments and equal lymph flows returning to the plasma. This greatly constrains the model such that each protein is characterized by only two adjustable parameters (plasma clearance and sieving factor). In addition to accurately fitting the plasma kinetics, the model can accurately describe the tissue and lymph protein PK. For example, it can describe the thoracic duct lymph protein concentration following an intravenous infusion or the plasma concentration following a subcutaneous tissue injection. This simple model provides a satisfactory framework for the PK of 12 of the 13 proteins investigated. The glycoprotein intestinal alkaline phosphatase is the exception, requiring the addition of a liver recycling compartment involving the asialoglycoprotein receptor.
多种细胞酶（丙氨酸转氨酶、天冬氨酸转氨酶、碱性磷酸酶、淀粉酶等）血浆浓度升高通常用作一系列病症的常规筛查测试。通常认为浓度升高是由于向血浆输送的速率增加所致。诸如代谢或排泄减少或血管外分布改变等因素通常被忽略。作为详细分析所有导致血浆酶水平改变的因素的前奏，我们回顾了描述13种常用测量血浆蛋白的药代动力学（PK）的相关文献，并开发了一个PK模型，该模型对所有数据提供了简单的生理学描述。我们的模型从先前为白蛋白开发的通用三室、六参数系统开始，并根据从血浆到两个组织隔室的单向筛分蛋白对流体积流以及返回血浆的等量淋巴流来解释通量。这极大地限制了模型，使得每种蛋白仅由两个可调参数（血浆清除率和筛分因子）表征。除了准确拟合血浆动力学外，该模型还可以准确描述组织和淋巴蛋白的PK。例如，它可以描述静脉输注后胸导管淋巴蛋白浓度或皮下组织注射后血浆浓度。这个简单的模型为所研究的13种蛋白中的12种的PK提供了一个令人满意的框架。糖蛋白肠碱性磷酸酶是个例外，需要添加一个涉及去唾液酸糖蛋白受体的肝脏再循环隔室。
