Animal models

Male C57BL/6 mice, male C57 albino mice

Preparation Method

Two peripheral TPH inhibitors, LP-920540 and telotristat etiprate were given orally to mice. Effects were measured on 5-HT levels in the gut, blood and brain, 5-HT immunoreactivity in the ENS, gastrointestinal motility and severity of trinitrobenzene sulfonic acid (TNBS)-induced colitis.

Dosage form

15, 50, 150, 300 mg/kg, Administered intragastrically

Applications

Telotristat etiprate reduced 5-HT significantly in the gut and blood but not in the brain. Telotristat etiprate cannot decrease 5-HT immunoreactive neurons or fibres in the myenteric plexus or altered total gastrointestinal transit time, colonic motility or gastric emptying in mice.

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 IC₅₀of 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