title: Serotonin biosynthesis as a predictive marker of serotonin pharmacodynamics and disease-induced dysregulation.
abstract: The biogenic amine serotonin (5-HT) is a multi-faceted hormone that is synthesized from dietary tryptophan with the rate limiting step being catalyzed by the enzyme tryptophan hydroxylase (TPH). The therapeutic potential of peripheral 5-HT synthesis inhibitors has been demonstrated in a number of clinical and pre-clinical studies in diseases including carcinoid syndrome, lung fibrosis, ulcerative colitis and obesity. Due to the long half-life of 5-HT in blood and lung, changes in steady-state levels are slow to manifest themselves. Here, the administration of stable isotope labeled tryptophan (heavy "h-Trp") and resultant in vivo conversion to h-5-HT is used to monitor 5-HT synthesis in rats. Dose responses for the blockade of h-5-HT appearance in blood with the TPH inhibitors L-para-chlorophenylalanine (30 and 100 mg/kg) and telotristat etiprate (6, 20 and 60 mg/kg), demonstrated that the method enables robust quantification of pharmacodynamic effects on a short time-scale, opening the possibility for rapid screening of TPH1 inhibitors in vivo. In the bleomycin-induced lung fibrosis rat model, the mechanism of lung 5-HT increase was investigated using a combination of synthesis and steady state 5-HT measurement. Elevated 5-HT synthesis measured in the injured lungs was an early predictor of disease induced increases in total 5-HT.
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Richard W D
authors.initials: RW
authors.lastname: Welford
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Magali
authors.initials: M
authors.lastname: Vercauteren
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Annette
authors.initials: A
authors.lastname: Trébaul
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Christophe
authors.initials: C
authors.lastname: Cattaneo
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Doriane
authors.initials: D
authors.lastname: Eckert
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Garzotti
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Patrick
authors.initials: P
authors.lastname: Sieber
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Segrestaa
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Studer
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Groenen
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, CH-4123 Allschwil, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Nayler
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005355:Fibrosis / Q000473:pathology; D007553:Isotope Labeling; D017563:Lung Diseases, Interstitial / Q000473:pathology; D051381:Rats; D012701:Serotonin / Q000096:biosynthesis*; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics*; D014364:Tryptophan / Q000008:administration & dosage; D014365:Tryptophan Hydroxylase / Q000037:antagonists & inhibitors
chemical_list: D017366:Serotonin Receptor Agonists; D012701:Serotonin; D014364:Tryptophan; D014365:Tryptophan Hydroxylase