Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Basic Clin Pharmacol Toxicol. 2010 Mar;106(3):215-20. doi: 10.1111/j.1742-7843.2009.00517.x. Epub 2009 Dec 30.
Active-site concentrations can be defined as the concentrations of unbound, pharmacologically active substances at the site of action. In contrast, the total concentrations of the drug in plasma/organ/tissue also include the protein- or tissue-bound molecules that are pharmacologically inactive. Plasma and whole tissue concentrations are used as predictors of effects and side effects because of their ease of sampling, while the concentrations of unbound drug in tissue are more difficult to measure. However, with the introduction of microdialysis and subsequently developed techniques, it has become possible to test the free drug hypothesis. The brain is an interesting organ in this regard because of the presence of the blood-brain barrier with its tight junctions and active efflux and influx transporters. We have proposed that research into brain drug delivery be divided into three main areas: the rate of delivery (PS, CL(in)), the extent of delivery (K(p,uu)) and the non-specific affinity of the drug to brain tissue, described by the volume of distribution of unbound drug in the brain (V(u,brain)). In this way, the concentration of unbound drug at the target site can be estimated from the total brain concentration and the plasma concentration after measuring the fraction of unbound drug. Results so far fully support the theory that active site concentrations are the best predictors when active transport is present. However, there is an urgent need to collect more relevant data for predicting active site concentrations in tissues with active transporters in their plasma membranes.
活性部位浓度可以定义为作用部位未结合的、具有药理活性的物质的浓度。相比之下，药物在血浆/器官/组织中的总浓度还包括在蛋白或组织中结合的、无药理活性的分子。由于其易于采样，血浆和全组织浓度被用作预测效果和副作用的指标，而组织中未结合药物的浓度则更难测量。然而，随着微透析技术的引入以及随后开发的技术，已经可以测试游离药物假说。在这方面，大脑是一个有趣的器官，因为它存在血脑屏障，其紧密连接和主动外排和内流转运体。我们提出，将脑内药物传递的研究分为三个主要领域：传递速度（PS、CL(in)）、传递程度（K(p,uu)）和药物对脑组织的非特异性亲和力，由脑中未结合药物的分布容积（V(u,brain)）描述。通过这种方式，可以从总脑浓度和测量未结合药物分数后的血浆浓度来估计靶部位未结合药物的浓度。到目前为止，结果完全支持这样的理论，即当存在主动转运时，活性部位浓度是最好的预测指标。然而，迫切需要收集更多相关数据，以预测具有主动转运体的组织中的活性部位浓度。
