Albany College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences, 106 New Scotland Avenue, Albany, NY 12208, United States.
Albany College of Pharmacy and Health Sciences, Department of Pharmaceutical Sciences, 106 New Scotland Avenue, Albany, NY 12208, United States.
J Pharm Sci. 2021 Oct;110(10):3331-3344. doi: 10.1016/j.xphs.2021.05.018. Epub 2021 Jun 2.
Over the last few decades, scientists and clinicians have often focused their attention on the unbound fraction of drugs as an indicator of efficacy and the eventual outcome of drug treatments for specific illnesses. Typically, the total drug concentration (bound and unbound) in plasma is used in clinical trials to assess a compound's efficacy. However, the free concentration of a drug tends to be more closely related to its activity and interaction with the body. Thus far, measuring the unbound concentration has been a challenge. Several mechanistic models have attempted to solve this problem by estimating the free drug fraction from available data such as total drug and binding protein concentrations. The aims of this review are first, to give an overview of the methods that have been used to date to calculate the unbound drug fraction. Second, to assess the pharmacokinetic parameters affected by changes in drug protein binding in special populations such as pediatrics, the elderly, pregnancy, and obesity. Third, to review alterations in drug protein binding in some selected disease states and how these changes impact the clinical outcomes for the patients; the disease states include critical illnesses, transplantation, renal failure, chronic kidney disease, and epilepsy. And finally, to discuss how various disease states shift the ratio of unbound to total drug and the consequences of such shifts on dosing adjustments and reaching the therapeutic target.
在过去的几十年中，科学家和临床医生经常将注意力集中在药物的未结合部分作为药物治疗特定疾病的疗效和最终结果的指标。通常，在临床试验中使用血浆中的总药物浓度（结合和未结合）来评估化合物的疗效。然而，药物的游离浓度往往与其活性和与身体的相互作用更为密切相关。到目前为止，测量未结合浓度一直是一个挑战。几种机制模型试图通过从总药物和结合蛋白浓度等可用数据估算游离药物分数来解决这个问题。本文的目的首先是概述迄今为止用于计算未结合药物分数的方法。其次，评估药物蛋白结合变化在特殊人群（如儿科、老年人、妊娠和肥胖）中对药代动力学参数的影响。第三，回顾一些选定疾病状态下药物蛋白结合的改变以及这些改变如何影响患者的临床结果；这些疾病状态包括危重病、移植、肾衰竭、慢性肾病和癫痫。最后，讨论各种疾病状态如何改变游离药物与总药物的比例，以及这种变化对剂量调整和达到治疗目标的影响。
