Mendes Pedro, Oliver Stephen G, Kell Douglas B
School of Computer Science; Manchester Institute of Biotechnology, The University of Manchester, 131 Princess St, Manchester M1 7DN, UK; Centre for Synthetic Biology of Fine and Speciality Chemicals (SYNBIOCHEM), The University of Manchester, 131, Princess St, Manchester M1 7DN, United Kingdom; Center for Quantitative Medicine, University of Connecticut, UConn Health, 263 Farmington Avenue, Farmington, CT 06030-6033, USA.
Cambridge Systems Biology Centre; Dept of Biochemistry, University of Cambridge, Sanger Building, 80 Tennis Court Road, Cambridge CB2 1GA, UK.
Trends Pharmacol Sci. 2015 Nov;36(11):710-723. doi: 10.1016/j.tips.2015.07.006. Epub 2015 Nov 1.
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.
该期刊最近发表的一篇论文认为，所报道的药物转运体的表达水平、催化常数（kcat）和米氏常数（Km）可用于估计药物通过Caco-2细胞的通量仅由蛋白质转运体介导的可能性。实际上得出的结论是，如果5种这样的转运体“随机”起作用，它们在35%的时间内可解释所测试的通透性最高的药物（维拉帕米）的通量。然而，文中引用的维拉帕米的通透性数值异常高；这种药物以及其他药物的通透性要低得多。即便对于所宣称的通透性，我们发现单个“随机”转运体在42%的时间内可解释通量，且两个转运体在90%的时间内可达到10·10(-6)厘米·秒(-1)。参数优化方法表明，即使是单个转运体也可解释通透性最高的药物在Caco-2细胞中的摄取。总体而言，“（药物的）磷脂双分子层扩散可忽略不计”这一观点并未被基于转运体的“可能”通量计算所推翻。
