LX1606 Hippurate (Telotristat etiprate) (Synonyms: LX 1032 hippurate, LX 1606 hippurate)

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