The permeation of small molecules across biological membranes is a crucial process that lies at the heart of life. Permeation is involved not only in the maintenance of homeostasis at the cell level but also in the absorption and biodistribution of pharmacologically active substances throughout the human body. Membranes are formed by phospholipid bilayers that represent an energy barrier for permeating molecules. Crossing this energy barrier is assumed to be a singular event, and permeation has traditionally been described as a first-order kinetic process, proportional only to the concentration gradient of the permeating substance. For a given membrane composition, permeability was believed to be a unique property dependent only on the permeating molecule itself. We provide experimental evidence that this long-held view might not be entirely correct. Liposomes were used in copermeation experiments with a fluorescent probe, where simultaneous permeation of two substances occurred over a single phospholipid bilayer. Using an assay of six commonly prescribed drugs, we have found that the presence of a copermeant can either enhance or suppress the permeation rate of the probe molecule, often more than 2-fold in each direction. This can have significant consequences for the pharmacokinetics and bioavailability of commonly prescribed drugs when used in combination and provide new insight into so-far unexplained drug–drug interactions as well as changing the perspective on how new drug candidates are evaluated and tested.

中文翻译：

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脂质体共渗透测定揭示了常用处方药物的意外膜相互作用

小分子穿过生物膜的渗透是生命核心的关键过程。渗透不仅涉及细胞水平稳态的维持，还涉及药理活性物质在整个人体的吸收和生物分布。膜由磷脂双层形成，磷脂双层代表渗透分子的能量屏障。跨越这个能量势垒被认为是一个单一事件，渗透传统上被描述为一级动力学过程，仅与渗透物质的浓度梯度成正比。对于给定的膜成分，渗透性被认为是仅取决于渗透分子本身的独特性质。我们提供的实验证据表明，这种长期持有的观点可能并不完全正确。脂质体用于与荧光探针的共渗透实验，其中两种物质同时渗透在单个磷脂双层上。通过对六种常用药物的分析，我们发现助剂的存在可以增强或抑制探针分子的渗透率，通常在每个方向上提高 2 倍以上。当联合使用时，这可能会对常用处方药物的药代动力学和生物利用度产生重大影响，并为迄今为止无法解释的药物相互作用提供新的见解，并改变新候选药物评估和测试方式的观点。