Fitting Transporter Activities to Cellular Drug Concentrations and Fluxes: Why the Bumblebee Can Fly.
Fitting Transporter Activities to Cellular Drug Concentrations and Fluxes: Why the Bumblebee Can Fly.
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DOI：
10.1016/j.tips.2015.07.006
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发表时间：
2015-11
影响因子：
13.8
通讯作者：
Kell DB
中科院分区：
文献类型：
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作者：
Mendes P;Oliver SG;Kell DB
该杂志最近的一篇论文认为，药物转运蛋白的报告表达水平，kcat和Km可用于估计通过Caco-2细胞的药物通量仅由蛋白转运蛋白引起的可能性。事实上，得出的结论是，如果五个这样的转运蛋白“随机”贡献，它们可以解释35%的时间内最具渗透性的测试药物（维拉帕米）的通量。然而，维拉帕米的渗透性值异常高;这种药物和其他药物的渗透性要低得多。即使对于声称的渗透率，我们发现单个“随机”转运体可以在42%的时间内解释通量，而两个转运体可以在90%的时间内达到10 · 10−6 cm·s−1。参数优化方法表明，即使是一个单一的转运蛋白可以解释Caco-2药物吸收的最具渗透性的药物。总的来说，“磷脂双层扩散（药物）是可以忽略不计的”的建议是不成立的“可能的”基于转运的通量的计算。关于细胞跨膜药物转运通过任何磷脂双层区域发生或仅由转运蛋白介导的相对程度，最近一直存在争议。许多最近的证据表明（也许令人惊讶），磷脂双层扩散可以忽略不计。该杂志最近的一篇文章表明，已知转运蛋白的表达谱和动力学可能不足以解释Caco-2细胞中仅通过转运蛋白的最活跃的药物通量（维拉帕米和普萘洛尔）。我们用我们自己的模拟表明，事实并非如此，特别是当考虑到进化选择时，并且Haldom关系直接解释了方向差异，即使是平衡转运蛋白。典型的蛋白转运蛋白单独可以很容易地解释Caco-2细胞中测量的药物通量。
A recent paper in this journal argued that reported expression levels, kcat and Km for drug transporters could be used to estimate the likelihood that drug fluxes through Caco-2 cells could be accounted for solely by protein transporters. It was in fact concluded that if five such transporters contributed ‘randomly’ they could account for the flux of the most permeable drug tested (verapamil) 35% of the time. However, the values of permeability cited for verapamil were unusually high; this and other drugs have much lower permeabilities. Even for the claimed permeabilities, we found that a single ‘random’ transporter could account for the flux 42% of the time, and that two transporters can achieve 10 · 10−6 cm·s−1 90% of the time. Parameter optimisation methods show that even a single transporter can account for Caco-2 drug uptake of the most permeable drug. Overall, the proposal that ‘phospholipid bilayer diffusion (of drugs) is negligible’ is not disproved by the calculations of ‘likely’ transporter-based fluxes. There has been recent debate as to the relative extents to which cellular transmembrane drug transports occur through any phospholipid bilayer region or is transporter-mediated only. Much recent evidence suggests (perhaps surprisingly) that phospholipid bilayer diffusion is negligible. A recent article in this journal suggested that the expression profile and kinetics of known transporters might not be adequate to explain the most active drug fluxes (of verapamil and propranolol) in Caco-2 cells via transporters only. We show with our own simulations that this is not in fact the case, especially when evolutionary selection is taken into account, and that the Haldane relation accounts straightforwardly for directional differences, even for equilibrative transporters. Typical protein transporters alone can easily account for measured drug fluxes in Caco-2 cells.