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首页> 外文期刊>Life sciences >In vitro stability and intestinal absorption characteristics of hexapeptide endothelin receptor antagonists.
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In vitro stability and intestinal absorption characteristics of hexapeptide endothelin receptor antagonists.

机译：六肽内皮素受体拮抗剂的体外稳定性和肠道吸收特性。

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摘要

Endothelins are potent vasoconstrictor peptides which have a wide range of tissue distribution and three receptor subtypes (ET(A), ET(B) and ET(C)). Among the linear hexapeptide ET(A)/ET(B) receptor antagonists, PD 145065 (Ac-D-Bhg-L-Leu-L-Asp-L-Ile-L-Ile-L-Trp, Bhg = (10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-Gly) and PD 156252 (Ac-D-Bhg-L-Leu-L-Asp-L-Ile-(N-methyl)-L-Ile-L-Trp) were selected to evaluate the metabolic stability and intestinal absorption in the absence and/or in the presence of protease inhibitors. In vitro stability of both compounds was investigated in fresh plasma, lumenal perfusate, intestinal and liver homogenates. PD 156252 was more stable than PD 145065 in intestinal tissue homogenate (63.4% vs. 20.5% remaining) and liver homogenate (74.4% vs. 35.5% remaining), while both compounds showed relatively good stability in the fresh plasma (94.5% vs. 86.7% remaining) and lumenal perfusate (85.8% vs. 72.3% remaining). The effect of protease inhibitors on the degradation of PD 145065 and PD 156252 was also investigated. Amastatin, thiorphan, chymostatin and the mixture of these three inhibitors were effective in reducing the degradation of both compounds. The pharmacokinetic parameters of PD 156252, calculated by using a non-compartmental model, were 6.95 min (terminal half-life), 191 mL (Vss), and 25.5 mL/min (Cl(tot)) after intravenous administration in rats. The intestinal absorption of PD 156252 in rats was evaluated in the absence and/or in the presence of protease inhibitors. The results indicate that the major elimination pathway of PD 156252 appears to be the biliary excretion and protease inhibitors increase the intestinal absorption of PD 156252 through increasing metabolic stability.
机译：内皮素是有效的血管收缩肽，具有广泛的组织分布范围和三种受体亚型（ET（A），ET（B）和ET（C））。在线性六肽ET（A）/ ET（B）受体拮抗剂中，PD 145065（Ac-D-Bhg-L-Leu-L-Asp-Lle-L-Ile-L-Trp，Bhg =（10， 11-二氢-5H-二苯并[a，d]环庚基-5-基）-Gly）和PD 156252（Ac-D-Bhg-L-Leu-L-Asp-L-Ile-（N-甲基）-L选择-Ile-L-Trp）以评估在不存在和/或存在蛋白酶抑制剂的情况下的代谢稳定性和肠吸收。在新鲜血浆，腔内灌注液，肠和肝匀浆中研究了这两种化合物的体外稳定性。 PD 156252在肠组织匀浆（分别为63.4％对20.5％）和肝匀浆（74.4％对35.5％）中比PD 145065更稳定，而两种化合物在新鲜血浆中均显示出相对较好的稳定性（94.5％对20.5％）。剩余86.7％）和腔内灌注液（85.8％比剩余72.3％）。还研究了蛋白酶抑制剂对PD 145065和PD 156252降解的影响。阿马斯汀，噻吩，糜蛋白酶和这三种抑制剂的混合物可有效减少两种化合物的降解。通过使用非房室模型计算得出的PD 156252的药代动力学参数为大鼠静脉内给药后的6.95分钟（终末半衰期），191 mL（Vss）和25.5 mL / min（Cl（tot））。在不存在蛋白酶抑制剂和/或存在蛋白酶抑制剂的情况下，评估大鼠中PD 156252的肠吸收。结果表明，PD 156252的主要消除途径似乎是胆汁排泄，蛋白酶抑制剂通过增加代谢稳定性来增加PD 156252的肠道吸收。

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