TY - JOUR
T1 - LX-1031, a tryptophan 5-hydroxylase inhibitor, and its potential in chronic diarrhea associated with increased serotonin
AU - Camilleri, M.
PY - 2011/3
Y1 - 2011/3
N2 - LX-1031 is an oral, small molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10-8-10-7molL-1 range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250-750mg q.i.d.; the median T1/2 for elimination is ∼20h, and repeat administration for 14days doubles Cmax. In ascending-single-dose and multiple-dose (14days) trials in healthy volunteers, LX-1031, 2-4gday-1 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by Day 5, and persisting over the 14day exposure. There are no dose-limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4weeks) and improved stool consistency with lower urinary 5-HIAA excretion. LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.
AB - LX-1031 is an oral, small molecule tryptophan 5-hydroxylase (TPH) inhibitor that reduces serotonin (5-HT) synthesis peripherally. It has potential for illnesses characterized by excess 5-HT, such as diarrhea-predominant irritable bowel syndrome (IBS-D) and carcinoid diarrhea. In vitro, inhibition of TPH1 occurred in 10-8-10-7molL-1 range. In vivo in rodents, LX-1031 has no effect on brain 5-HT while dose-dependently reducing 5-HT, particularly in the small bowel. After oral LX1031 in humans, systemic exposure is very low, plasma concentrations are linear in dose range 250-750mg q.i.d.; the median T1/2 for elimination is ∼20h, and repeat administration for 14days doubles Cmax. In ascending-single-dose and multiple-dose (14days) trials in healthy volunteers, LX-1031, 2-4gday-1 significantly reduced urinary 5-hydroxyindoleacetic acid (5-HIAA) starting by Day 5, and persisting over the 14day exposure. There are no dose-limiting toxicities in healthy subjects or remarkable adverse effects in clinical trials to date. Over a 28-day treatment period, LX-1031 was associated with improved weekly global scores (2/4weeks) and improved stool consistency with lower urinary 5-HIAA excretion. LX-1031 appears promising for chronic diarrhea associated with increased 5-HT expression including IBS-D. Optimal doses, efficacy and safety in IBS clinical trials need to be fully elucidated; low systemic exposure, selectivity for TPH1 over TPH2, and lack of effect on brain 5-HT in several species suggest that LX-1031 is unlikely to cause affective disorders.
KW - Carcinoid
KW - Irritable bowel
UR - http://www.scopus.com/inward/record.url?scp=79551714477&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=79551714477&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2982.2010.01643.x
DO - 10.1111/j.1365-2982.2010.01643.x
M3 - Review article
C2 - 21159063
AN - SCOPUS:79551714477
SN - 1350-1925
VL - 23
SP - 193
EP - 200
JO - Neurogastroenterology and Motility
JF - Neurogastroenterology and Motility
IS - 3
ER -