LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin.
LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin.
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DOI：
10.1111/j.1365-2982.2010.01643.x
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发表时间：
2011-03
影响因子：
3.5
通讯作者：
Camilleri M
中科院分区：
文献类型：
--
作者：
Camilleri M
LX-1031是一种口服小分子色氨酸5-羟化酶（TPH）抑制剂，可降低周围血清素（5-HT）的合成。它有可能导致以过量5-羟色胺为特征的疾病，如腹泻为主的肠易激综合征（IBS-D）和类癌性腹泻。在体外，TPH1在10−8 ~ 10−7 M范围内受到抑制。在啮齿类动物体内，LX-1031对大脑5-HT没有影响，但剂量依赖性地降低了5-HT，特别是在小肠中。人口服LX1031后，全身暴露量非常低，血浆浓度在剂量范围内为250 mg QD至750 mg QD；消除的中位T1/2为~20小时，重复给药14天，Cmax加倍。在健康志愿者的上升单剂量和多剂量（14天）试验中，LX-1031 2g-4g/天显著降低尿5-羟基吲哚乙酸（5- hiaa），从第5天开始，并持续14天。迄今为止，在健康受试者中没有剂量限制性毒性或临床试验中显著的不良反应。在28天的治疗期内，LX-1031改善了每周总体评分（2/4周），改善了粪便一致性，降低了尿5-HIAA排泄量。LX-1031似乎有望治疗与5-HT表达增加相关的慢性腹泻，包括IBS-D。肠易激综合征临床试验的最佳剂量、疗效和安全性需要充分阐明；在一些物种中，低系统性暴露、TPH1对TPH2的选择性以及对脑5-羟色胺缺乏影响表明LX-1031不太可能引起情感性障碍。
LX-1031 is an oral, small-molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10−8 – 10−7 M range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250 mg QD to 750 mg QID; the median T1/2 for elimination is ~20 hrs, and repeat administration for 14 days doubles Cmax. In ascending-single-dose and multiple dose (14 day) trials in healthy volunteers, LX-1031 2g-4g/day significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by day 5, and persisting over the 14 day exposure. There are no dose limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4 weeks) and improved stool consistency with lower urinary 5-HIAA excretion. LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.
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