Department of Chemistry, Pharmaqam/NanoQAM, Université du Québec à Montréal, P.O. Box 8888, Downtown Station, Montreal, QC, H3C 3P8, Canada.
Eur Biophys J. 2010 Nov;39(12):1637-47. doi: 10.1007/s00249-010-0622-y. Epub 2010 Aug 27.
Excipients in the pharmaceutical formulation of oral drugs are notably employed to improve drug stability. However, they can affect drug absorption and bioavailability. Passive transport through intestinal cell walls is the main absorption mechanism of drugs and, thus, involves an interaction with the membrane lipids. Therefore in this work, the effect of the excipient NaHCO(3) on the interaction of the anticholesterolemic drug fluvastatin sodium (FS) with membrane phospholipids was investigated by (1)H NMR and FTIR spectroscopy. Sodium bicarbonate is often combined with fluvastatin for oral delivery to prevent its degradation. We have used model DMPC/DMPS membranes to mimic the phospholipid content of gut cell membranes. The results presented in this work show a 100% affinity of FS for the membrane phospholipids that is not modified by the presence of the excipient. However, NaHCO(3) is shown to change the interaction mechanism of the drug. According to our data, FS enters the DMPC/DMPS bilayer interface by interacting with the lipids' polar headgroups and burying its aromatic moieties into the apolar core. Moreover, lipid segregation takes place between the anionic and zwitterionic lipids in the membranes due to a preferential interaction of FS with phosphatidylserines. The excipient counteracts this favored interaction without affecting the drug affinity and location in the bilayer. This work illustrates that preferential interactions with lipids can be involved in passive drug permeation mechanisms and gives evidence of a possible nonpassive role of certain excipients in the interaction of drugs with membrane lipids.
药物制剂中的辅料主要用于提高药物稳定性。然而，它们会影响药物的吸收和生物利用度。药物通过肠壁细胞的被动转运是药物吸收的主要机制，因此涉及与膜脂质的相互作用。因此，在这项工作中，通过（1）H NMR 和 FTIR 光谱研究了赋形剂 NaHCO（3）对降胆固醇药物 fluvastatin sodium（FS）与膜磷脂相互作用的影响。碳酸氢钠通常与 fluvastatin 结合用于口服给药以防止其降解。我们使用模型 DMPC/DMPS 膜来模拟肠细胞膜的磷脂含量。这项工作中的结果表明，FS 对膜磷脂具有 100%的亲和力，赋形剂的存在不会改变这种亲和力。然而，NaHCO（3）被证明改变了药物的相互作用机制。根据我们的数据，FS 通过与脂质的极性头基相互作用并将其芳族部分埋入非极性核心来进入 DMPC/DMPS 双层界面。此外，由于 FS 与磷脂酰丝氨酸的优先相互作用，在膜中发生阴离子和两性离子脂质的脂质分离。赋形剂抵消了这种有利的相互作用，而不影响药物在双层中的亲和力和位置。这项工作表明，与脂质的优先相互作用可能参与被动药物渗透机制，并为某些赋形剂在药物与膜脂质相互作用中的非被动作用提供了证据。
