Emmons Gary, Rowland Malcom
Drug Disposition, Safety & Animal Research, sanofi-aventis, Bridgewater, NJ, USA.
Bioanalysis. 2010 Nov;2(11):1791-6. doi: 10.4155/bio.10.159.
In the past few years there has been a large increase in the reporting of the use of dried blood spots (DBS) in drug development. Most of these reports pertain to the technological improvements that have allowed for drug concentration measurements from microliter volumes of sample, issues concerning method development, and exploration of the technique, into other areas such as measurement of macromolecules and metabolite identification. One area that has received less attention and is the subject of this commentary concerns the pharmacokinetic issues that arise from using DBS as opposed to plasma, the mainstay matrix. Measurements of drug concentrations from either plasma or dbs are almost always the sum of bound and unbound drug, but it is the unbound drug in plasma (plasma water) that is the relevant driver of essentially all pharmacokinetic and pharmacodynamic events. Therefore, the critical assumption made is constancy in fraction unbound for plasma, and additionally for blood, constancy of hematocrit and blood cell affinity. Often these assumptions are reasonable and either matrix suffices, but not always. Then the value of one matrix over the other depends on the magnitude of the blood-to-plasma concentration ratio of drug, its clearance and the cause of the deviation from constancy. Additional considerations are the kinetics of distribution within blood and those arising when the objective is assessment or comparison of bioavailability. Most of these issues can be explored and addressed in vitro prior to the main drug development program.
在过去几年中，药物研发中关于使用干血斑（DBS）的报告大幅增加。这些报告大多涉及技术改进，这些改进使得能够从微升体积的样本中测量药物浓度、方法开发相关问题以及该技术在其他领域的探索，如大分子测量和代谢物鉴定。一个较少受到关注且是本评论主题的领域是与使用DBS而非血浆（主要基质）相关的药代动力学问题。从血浆或DBS中测量药物浓度几乎总是结合型和游离型药物的总和，但血浆（血浆水）中的游离型药物才是几乎所有药代动力学和药效学事件的相关驱动因素。因此，关键假设是血浆中游离分数恒定，此外对于血液，血细胞比容和血细胞亲和力恒定。通常这些假设是合理的，两种基质都足够，但并非总是如此。那么一种基质相对于另一种基质的价值取决于药物的血药浓度与血浆浓度之比、其清除率以及偏离恒定的原因。其他需要考虑的因素是血液内的分布动力学以及在评估或比较生物利用度时出现的情况。这些问题大多可以在主要药物研发项目之前通过体外研究来探索和解决。
