Delie F, Couvreur P, Nisato D, Michel J B, Puisieux F, Letourneux Y
Laboratoire de Physico-Chimie, Pharmacotechnie et Biopharmacie, URA CNRS 1218, Faculté de Pharmacie, Catenay-Malabry, France.
Pharm Res. 1994 Aug;11(8):1082-7. doi: 10.1023/a:1018916311111.
A diglyceride derivative of a pentapeptide renin inhibitor, the 1,3-dipalmitoyl-[Iva-Phe-Nle-Sta-Ala-Sta-acetyl]-glycerol was synthesized and tested in vitro as a potential prodrug for oral administration. The ability of the diglyceride analog to inhibit the renin activity was equivalent to that of the parent peptide after predigestion with pancreatic lipase. Furthermore, the presence of the palmitoyl groups was found to induce, in vitro, an efficient protection of the peptide from gastric and intestinal hydrolysis. During incubation with intestinal and gastric fluids, and with alpha-chymotrypsin and pancreatic lipase, the glycerolipidic derivative was more stable than the peptide alone. These results support the use of glycerolipidic prodrug for oral administration of peptides.
一种五肽肾素抑制剂的甘油二酯衍生物，即1,3 - 二棕榈酰 - [异缬氨酸 - 苯丙氨酸 - 正亮氨酸 - 司他汀 - 丙氨酸 - 司他汀 - 乙酰基] - 甘油被合成，并作为口服给药的潜在前药进行体外测试。在用胰脂肪酶预消化后，甘油二酯类似物抑制肾素活性的能力与母体肽相当。此外，发现棕榈酰基的存在能在体外有效保护该肽免受胃和肠道水解。在与肠液、胃液、α - 胰凝乳蛋白酶和胰脂肪酶一起孵育时，甘油脂质衍生物比单独的肽更稳定。这些结果支持使用甘油脂质前药进行肽的口服给药。
