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首页> 外文期刊>The Journal of Pharmacology and Experimental Therapeutics: Official Publication of the American Society for Pharmacology and Experimental Therapeutics >Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation
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Pharmacologic properties, metabolism, and disposition of linaclotide, a novel therapeutic peptide approved for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation

机译：利那洛肽的药理特性，代谢和处理方法，利那洛肽是一种新型治疗肽，已被批准用于治疗便秘和慢性特发性便秘的肠易激综合征

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摘要

Linaclotide, a potent guanylate cyclase C agonist, is a therapeutic peptide approved in the United States for the treatment of irritable bowel syndrome with constipation and chronic idiopathic constipation. We present for the first time the metabolism, degradation, and disposition of linaclotide in animals and humans. We examined the metabolic stability of linaclotide in conditions that mimic the gastrointestinal tract and characterized the metabolite MM-419447 (CCEYCCNPACTGC), which contributes to the pharmacologic effects of linaclotide. Systemic exposure to these active peptides is low in rats and humans, and the low systemic and portal vein concentrations of linaclotide and MM-419447 observed in the rat confirmed both peptides are minimally absorbed after oral administration. Linaclotide is stable in the acidic environment of the stomach and is converted to MM-419447 in the small intestine. The disulfide bonds of both peptides are reduced in the small intestine, where they are subsequently proteolyzed and degraded. After oral administration of linaclotide, <1% of the dose was excreted as active peptide in rat feces and a mean of 3-5% in human feces; in both cases MM-419447 was the predominant peptide recovered. MM-419447 exhibits high-affinity binding in vitro to T84 cells, resulting in a significant, concentration-dependent accumulation of intracellular cyclic guanosine-3',5'-monophosphate (cGMP). In rat models of gastrointestinal function, orally dosed MM-419447 significantly increased fluid secretion into small intestinal loops, increased intraluminal cGMP, and caused a dose-dependent acceleration in gastrointestinal transit. These results demonstrate the importance of the active metabolite in contributing to linaclotide's pharmacology.
机译：利那洛肽是一种有效的鸟苷酸环化酶C激动剂，是美国批准的治疗性肽，可治疗便秘和慢性特发性便秘的肠易激综合症。我们首次介绍了利那洛肽在动物和人类中的代谢，降解和处置。我们在模拟胃肠道的条件下检查了利那洛肽的代谢稳定性，并表征了代谢产物MM-419447（CCEYCCNPACTGC），这有助于利那洛肽的药理作用。在大鼠和人类中，这些活性肽的全身暴露量很低，并且在大鼠中观察到的利那洛肽和MM-419447的低全身和门静脉浓度证实口服给药后两种肽的吸收最少。利那洛肽在胃的酸性环境中稳定，并在小肠中转化为MM-419447。两种肽的二硫键在小肠中均被还原，随后它们被蛋白水解并降解。口服利那洛肽后，<1％的剂量以活性肽的形式排泄在大鼠粪便中，人粪便的平均排泄率为3-5％;在这两种情况下，MM-419447都是回收的主要肽。 MM-419447在体外表现出与T84细胞的高亲和力结合，导致细胞内环状鸟苷3'，5'-单磷酸（cGMP）的浓度依赖性显着积累。在大鼠胃肠功能模型中，口服MM-419447可显着增加小肠环中的液体分泌，增加管腔内cGMP的含量，并在胃肠道运输中引起剂量依赖性的加速作用。这些结果证明了活性代谢物对利那洛肽的药理作用的重要性。

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