Burton P S, Conradi R A, Ho N F, Hilgers A R, Borchardt R T
Drug Delivery Systems Research, Pharmacia and Upjohn, Inc., Kalamazoo, MI 49001, USA.
J Pharm Sci. 1996 Dec;85(12):1336-40. doi: 10.1021/js960067d.
Successful drug development requires not only optimization of specific and potent pharmacological activity at the target site, but also efficient delivery to that site. Many promising new peptides with novel therapeutic potential for the treatment of AIDS, cardiovascular diseases, and CNS disorders have been identified, yet their clinical utility has been limited by delivery problems. Along with metabolism, a major factor contributing to the poor bioavailability of peptides is thought to be inefficient transport across cell membranes. At the present time, the reasons for this poor transport are poorly understood. To explore this problem, we have designed experiments focused on determining the relationship between peptide structure and peptide transport across various biological membranes both in vitro and in vivo. Briefly, peptides that varied systematically in chain length, lipophilicity, and amide bond number were prepared. Permeability results with these solutes support a model in which the principal determinant of peptide transport is the energy required to desolvate the polar amides in the peptide for the peptide to enter and diffuse across the cell membrane. Further impacting on peptide permeability is the presence of active, secretory transport systems present in the apical membrane of intestinal epithelial and brain endothelial cells. In Caco-2 cell monolayers, a model of the human intestinal mucosa, this pathway displayed substrate specificity, saturation, and inhibition. Similar results have been shown in vivo in both rat intestinal and blood-brain barrier absorption models. The presence of such systems serves as an additional transport barrier by returning a fraction of absorbed peptide back to the lumen.
成功的药物研发不仅需要在靶点部位优化特定且强效的药理活性，还需要有效地将药物递送至该部位。已经鉴定出许多有望用于治疗艾滋病、心血管疾病和中枢神经系统疾病的具有新型治疗潜力的新肽，然而它们的临床应用却因递送问题而受到限制。除代谢外，肽生物利用度差的一个主要因素被认为是跨细胞膜转运效率低下。目前，这种转运不佳的原因尚不清楚。为了探究这个问题，我们设计了实验，重点是确定肽结构与肽在体外和体内跨各种生物膜转运之间的关系。简而言之，制备了链长、亲脂性和酰胺键数量系统变化的肽。这些溶质的渗透性结果支持这样一种模型，即肽转运的主要决定因素是肽进入并扩散穿过细胞膜时使肽中极性酰胺去溶剂化所需的能量。肠道上皮细胞和脑内皮细胞顶膜中存在的主动分泌转运系统的存在进一步影响了肽的渗透性。在人肠黏膜模型Caco-2细胞单层中，该途径表现出底物特异性、饱和性和抑制性。在大鼠肠道和血脑屏障吸收模型的体内实验中也得到了类似的结果。这些系统的存在通过将一部分吸收的肽返回肠腔而成为额外的转运屏障。
