Tozaki H, Emi Y, Horisaka E, Fujita T, Yamamoto A, Muranishi S
Department of Biopharmaceutics, Kyoto Pharmaceutical University, Japan.
J Pharm Pharmacol. 1997 Feb;49(2):164-8. doi: 10.1111/j.2042-7158.1997.tb06773.x.
The objective of this study was to examine the metabolism of insulin and calcitonin, and their protection by various protease inhibitors, in the large intestine. Fresh caecal contents were prepared from non-fasted rats and the degradation of insulin and calcitonin was studied in a suspension of rat caecal contents, as a model of the content of the large intestine. Both insulin and calcitonin were metabolized in suspensions of rat caecal contents, but the degradation of calcitonin was much faster than that of insulin. The degradation of insulin was fastest at pH 6.8. Protease inhibitors such as camostat and aprotinin inhibited the degradation of insulin and calcitonin in rat caecal contents, which was consistent with the high chymotrypsin activity of these contents. These findings suggest that care should be taken when administering peptide drugs to the large intestine for colon-specific drug delivery because they can be degraded in rat caecal contents. Protease inhibitors might be useful for increasing the stability of these peptides in the large intestine, thereby improving their large-intestinal absorption to the systemic circulation.
本研究的目的是在大肠中检测胰岛素和降钙素的代谢情况，以及各种蛋白酶抑制剂对它们的保护作用。从非禁食大鼠制备新鲜盲肠内容物，并在大鼠盲肠内容物悬浮液中研究胰岛素和降钙素的降解情况，以此作为大肠内容物的模型。胰岛素和降钙素在大鼠盲肠内容物悬浮液中均会发生代谢，但降钙素的降解速度比胰岛素快得多。胰岛素在pH 6.8时降解最快。蛋白酶抑制剂如抑肽酶和抑肽素可抑制大鼠盲肠内容物中胰岛素和降钙素的降解，这与这些内容物中高糜蛋白酶活性一致。这些发现表明，在将肽类药物用于结肠特异性给药而投放到大肠时应谨慎，因为它们可能在大鼠盲肠内容物中被降解。蛋白酶抑制剂可能有助于提高这些肽在大肠中的稳定性，从而改善它们从大肠吸收进入体循环的情况。
