LX1606 Hippurate (Telotristat etiprate)

Telotristat etiprate is an ethyl ester prodrug which is hydrolyzed to its active moiety LP-778902 both in vivo and in vitro. Systemic exposure of Telotristat etiprate is relatively low, as the hydrolysis to the active moiety is rapid. LP-778902 is a potent inhibitor of TPH with an in vivo IC₅₀ of 0.028 μM.^[2]

In normal mice, Telotristat etiprate (administered once daily for 4 days at doses of 15-300 mg/kg/day) was found to reduce serotonin levels throughout the gastro-intestinal tract. These reductions occurred in a dose-dependent fashion with maximal effects observed with doses of Telotristat etiprate ≥150 mg/kg. No significant change in brain serotonin or 5-hydroxyindoleacetic acid (5-HIAA, a serotonin metabolite) was observed. Similar findings were seen in Sprague-Dawley rats. ^{[1, 2]}

Gastrointestinal motility studies were conducted in rat using the charcoal meal teat. There was a significant dose-related delay in both gastrointestinal transit and gastric emptying, associated with a reduction in blood serotine levels and proximal colon serotonin. ^[2]

Telotristat etiprate and its active moiety LP-778902 were tested for their inhibition of two related enzymes, phenylalanine and tyrosine hydroxylase, as well as several cytochrome P450 isoenzymes. This demonstrated that Telotristat etiprate is a highly specific inhibitor of TPH. ^[2]

References:
[1]. Margolis, Kara Gross et al. Pharmacological reduction of mucosal but not neuronal serotonin opposes inflammation in mouse intestine. Gut vol. 63,6 (2014): 928-37.
[2]. Lapuerta, P et al. Telotristat etiprate, a novel inhibitor of serotonin synthesis for the treatment of carcinoid syndrome. Clinical Investigation 2015 Vol.5 No.5 pp.447-456 ref.20

Telotristat etiprate 是一种乙酯前药,可在体内和体外水解为其活性部分 LP-778902。 Telotristat etiprate 的全身暴露相对较低,因为对活性部分的水解是快速的。 LP-778902 是一种有效的 TPH 抑制剂,体内 IC₅₀ 为 0.028 μM。^[2]

在正常小鼠中,发现 Telotristat etiprate（每天给药一次,剂量为 15-300 mg/kg/天,持续 4 天）可降低整个胃肠道的血清素水平。这些减低以剂量依赖方式发生,用 Telotristat etiprate ≥150 mg/kg 剂量观察到最大效应。未观察到脑血清素或 5-羟基吲哚乙酸（5-HIAA,一种血清素代谢物）的显着变化。在 Sprague-Dawley 大鼠中也观察到类似的发现。 ^{[1, 2]}

使用木炭餐奶嘴对大鼠进行了胃肠动力研究。胃肠道转运和胃排空均有显着的剂量相关延迟,这与血液血清素水平和近端结肠血清素的降低有关。 ^[2]

测试了 Telotristat etiprate 及其活性部分 LP-778902 对两种相关酶（苯丙氨酸和酪氨酸羟化酶）以及几种细胞色素 P450 同工酶的抑制作用。这表明 Telotristat etiprate 是一种高度特异性的 TPH 抑制剂。 ^[2]