Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2N8, Canada.
Clin Pharmacokinet. 2010 Jul;49(7):421-38. doi: 10.2165/11531190-000000000-00000.
For drugs that have a narrow therapeutic margin in their concentration-effect profile, blood concentration measurements can be an invaluable guide to the individualization of dosage regimens. For clinicians involved in therapeutic drug monitoring, background knowledge of basic pharmacokinetics related to drug behaviour with repeated dose regimens is crucial, especially recognition of the factors affecting the rate and extent of drug accumulation, which ultimately determine the steady-state drug concentrations in the blood. Much of the available literature describing accumulation focuses on average steady-state concentrations or its related parameter, the area under the blood/plasma concentration-time curve. However, in practice, for most drugs, it is the individual concentrations at different times within each dosing interval at steady state that can be more predictive of the effectiveness and/or toxicity of the drug. Furthermore, most reference textbooks describe accumulation in terms of drugs that follow a one-compartment model with bolus administration, whereas the mode of dose administration can have an impact on measures of accumulation in a manner that differs from intravascular bolus dosing. Additionally, the accumulation kinetics in the plasma are profoundly influenced by multicompartment or nonlinear pharmacokinetics. Another consideration in accumulation kinetics is how tissue concentrations might be influenced by repeated doses - which, as shown in this review, can have clinical ramifications. In this article, drug accumulation is reviewed in a comprehensive manner, and the influences of the route of administration, nonlinear elimination and tissue concentrations are discussed.
对于治疗窗较窄的药物，血药浓度测定可作为个体化剂量方案的重要指导。对于参与治疗药物监测的临床医生来说，了解与重复剂量方案相关的基本药代动力学的背景知识至关重要，尤其是要认识到影响药物蓄积速度和程度的因素，这些因素最终决定了血药稳态浓度。大量关于药物蓄积的可用文献主要集中在平均稳态浓度或其相关参数，即血药/血浆浓度-时间曲线下面积。然而，在实践中，对于大多数药物，更能预测药物有效性和/或毒性的是每个给药间隔内不同时间的个体浓度。此外，大多数参考书都是用单次静脉推注的一室模型来描述药物的蓄积情况，而给药方式可能会以不同于血管内推注的方式影响蓄积的衡量标准。此外，多室或非线性药代动力学对血浆中的蓄积动力学有深远的影响。在蓄积动力学中，另一个需要考虑的因素是重复给药如何影响组织浓度——正如本文综述所示，这可能会产生临床后果。本文全面回顾了药物蓄积，并讨论了给药途径、非线性消除和组织浓度的影响。
