中性肽链内切酶24.11和dipeptidyl肽酶IV都介质glucagon-like肽1的退化的犀牛猪。

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Plamboeck,霍尔斯特JJ,卡尔RD,执事CF

中性肽链内切酶24.11和dipeptidyl肽酶IV都介质glucagon-like肽1的退化的犀牛猪。

Diabetologia。2005年9月,48 (9):1882 - 90。Epub 2005年7月16日。

PubMed ID

16025254 (在PubMed

]

文摘

目的/假说:肠促胰岛素激素glucagon-like肽1 (GLP-1) antihyperglycaemic效果,但其治疗作用是有限的,其代谢不稳定。建立Dipeptidyl肽酶IV (DPP-IV)作为主要的灭活酶,但其他酶的作用尚不清楚。方法:candoxatril的影响,中性肽链内切酶的选择性抑制剂(NEP) 24.11, GLP-1药动学/药效学有或没有DPP-IV抑制在犀牛猪检查。结果:在GLP-1输液,candoxatril翻了一番c端免疫反应性,提高药物动力学(t(1/2) 2.3 + / - -0.1到8.8 + / - -1.2分钟;代谢清除率(MCR) 20.4 + / - -3.4到4.8 + / - -0.4 ml.kg (1)。分钟(1);p < 0.01),但没有影响完整GLP-1 (t(1/2) 1.4 + / - -0.1到1.6 + / - -0.1分钟;MCR 47.9 + / - -8.0到38.8 + / - -5.0 ml.kg (1) .min (1))。胰岛素反应静脉注射葡萄糖被candoxatril未受影响,但提高葡萄糖耐量(DeltaAUC(最低27 - 87)118 + / 5到74 + / -14 min.mmol.l (1);葡萄糖消除速率[k] 6.6 + / - -0.5到8.6 + / - -0.5%; p<0.05). When candoxatril was co-administered with valine pyrrolidide (a DPP-IV inhibitor), changes in C-terminal GLP-1 pharmacokinetics mirrored those seen when candoxatril alone was administered (t(1/2) 2.7+/-0.3 and 7.7+/-0.8 min; MCR 17.3+/-2.6 and 6.5+/-0.8 ml.kg(-1).min(-1) for valine pyrrolidide without and with candoxatril, respectively). However, intact GLP-1 pharmacokinetics were improved (t(1/2) 2.8+/-0.3 and 7.5+/-0.6 min; MCR 18.3+/-0.6 and 9.4+/-0.9 ml.kg(-1).min(-1); p<0.02), potentiating the antihyperglycaemic/insulinotropic effects of GLP-1 (glucose deltaAUC(min 27- 87) 103+/-8 to 62+/-14 min.mmol.l(-1); k 6.8+/-0.4 to 11.4+/-1.4%; insulin deltaAUC(min 27-87) 3,680+/-738 to 7,201+/-1,183 min.pmol.l(-1); p<0.05). CONCLUSIONS/INTERPRETATION: This study confirms a role for NEP-24.11 in GLP-1 metabolism in vivo, suggesting that up to 50% of GLP-1 entering the circulation may be degraded by NEP-24.11. Furthermore, combined inhibition of DPP-IV and NEP-24.11 is superior to DPP-IV inhibition alone in preserving intact GLP-1, which raises the possibility that the combination has therapeutic potential.

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药物靶点

药物	目标	类	生物	药理作用	行动
Candoxatril	Neprilysin	蛋白质	人类	是的	抑制剂	细节