Clinical Enteric Neuroscience Translational and Epidemiological Research Center, Mayo Clinic, Rochester, MN 55905, USA.
Neurogastroenterol Motil. 2011 Mar;23(3):193-200. doi: 10.1111/j.1365-2982.2010.01643.x. Epub 2010 Dec 15.
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) mol L(-1) 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 250-750 mg q.i.d.; the median T(1/2) for elimination is ∼ 20 h, and repeat administration for 14 days doubles C(max) . In ascending-single-dose and multiple-dose (14 days) trials in healthy volunteers, LX-1031, 2-4 g day(-1) 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.
LX-1031 是一种口服小分子色氨酸 5-羟化酶（TPH）抑制剂，可减少外周 5-羟色胺（5-HT）的合成。它具有治疗 5-HT 过度的疾病的潜力，如腹泻为主的肠易激综合征（IBS-D）和类癌腹泻。在体外，TPH1 的抑制作用发生在 10（-8）-10（-7）mol L（-1）范围内。在啮齿动物体内，LX-1031 对大脑 5-HT 没有影响，但剂量依赖性地减少 5-HT，特别是在小肠中。在人体中口服 LX-1031 后，全身暴露非常低，血浆浓度在 250-750mg q.i.d.的剂量范围内呈线性；消除的中位 T（1/2）约为 20 小时，重复给药 14 天可使 C（max）增加一倍。在健康志愿者的递增单剂量和多剂量（14 天）试验中，LX-1031，2-4g/d，从第 5 天开始显著降低尿 5-羟吲哚乙酸（5-HIAA），并在 14 天的暴露期间持续存在。在健康受试者中没有剂量限制毒性，也没有在临床试验中出现明显的不良反应。在 28 天的治疗期间，LX-1031 与每周全球评分的改善（2/4 周）和粪便一致性的改善以及尿 5-HIAA 排泄量的降低相关。LX-1031 有望用于治疗与 5-HT 表达增加相关的慢性腹泻，包括 IBS-D。在 IBS 临床试验中需要充分阐明最佳剂量、疗效和安全性；在几种物种中，低全身暴露、对 TPH1 的选择性高于 TPH2，以及对大脑 5-HT 无影响表明，LX-1031 不太可能引起情感障碍。
