Mechanism of Action of Telotristat

Physiology of Serotonin

Serotonin, also known as 5-hydroxytryptamine (5-HT), is predominantly produced by neuroendocrine cells, such as enterochromaffin cells, within the gastrointestinal tract. The synthesis of serotonin is a multistep process, beginning with the acquisition of the amino acid tryptophan from the bloodstream through carrier-mediated transport. Subsequently, tryptophan is converted into 5-hydroxytryptophan (5-HTP) via the activity of the enzyme tryptophan hydroxylase, a rate-limiting step in serotonin synthesis. The ensuing step involves the decarboxylation of 5-HTP through aromatic L-amino acid decarboxylase (AADC), which culminates in the production of serotonin. Upon synthesis, serotonin is stored in vesicles via the vesicular monoamine transporter (VMAT), awaiting release in response to neural impulses. Post-release, serotonin interacts with receptors in postsynaptic neurons and is metabolized by monoamine oxidase (MAO) and aldehyde dehydrogenase (ALDH), producing 5-hydroxyindoleacetaldehyde (5-HIAA), which is subsequently excreted through urine.

Mechanism of action of Telotristat

Telotristat, a tryptophan hydroxylase inhibitor, targets the enzymatic conversion of tryptophan to 5-hydroxytryptophan (5-HTP) in the serotonin synthesis pathway. It binds irreversibly to the active site of tryptophan hydroxylase, preventing the enzyme from catalyzing this pivotal conversion. This inhibitory action leads to a significant reduction in serotonin synthesis and release in the gastrointestinal tract. As a result, symptoms associated with carcinoid syndrome, a condition characterized by serotonin overproduction, are effectively alleviated.

Practice Guide for Telotristat

Telotristat, a medication often used in the management of carcinoid syndrome, is administered primarily by oral route and exhibits a favorable tolerance profile. It is commonly co-prescribed with somatostatin analogs, a distinct class of therapeutics also employed in the management of carcinoid syndrome. As a directive to treat diarrhea related to carcinoid syndrome, clinicians often initiate therapy with telotristat ethyl at a dose of 250 mg, administered three times daily with meals.

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