(+)-Trimebutine

387.5 g/mol

387.47

254-309-2

9RKX7S7WFY|U4UUZ24TRB

DTXSID4023707

A - Alimentary tract and metabolism

57.2 Ų

78-82|79.0 °C

Insoluble

|Warning|H302 (60%): Harmful if swallowed [Warning Acute toxicity, oral]|P261, P264, P270, P271, P273, P280, P301+P312, P302+P352, P304+P312, P304+P340, P312, P322, P330, P363, and P501|Aggregated GHS information provided by 13 companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Common gastrointestinal adverse effects include dry mouth, foul taste, diarrhea, dyspepsia, epigastric pain, nausea and constipation. Some CNS effects include drowsiness, fatigue, dizziness, hot/cold sensations and headaches. In case of overdosage, gastric lavage is recommended. Oral LD50 in mouse and rats is >5000 mg/kg and 2500 mg/kg in rabbits, respectively. Trimebutine is not reported to display teratogenic, mutagenic or carcinogenic potential.

Protein binding is minimal with 5% in vivo and in vitro to serum albumin.

Indicated for symptomatic treatment of irritable bowel syndrome (IBS) and treatment of postoperative paralytic ileus following abdominal surgery.

Trimebutine is a spasmolytic agent that acts directly on smooth muscle to modulate gastric motility. It shows a "dual function" that stimulates or inhibits spontaneous contractions depending on the concentration and prior contractile activity in the preparation. Targeting ion conductance that regulates GI motility, trimebutine inhibits the inward calcium currents and calcium-dependent potassium currents in a concentration-dependent manner. At lower concentrations (1-10uM), trimebutine depolarizes the resting membrane potential without affecting the amplitude of contractions, which is thought to be mediated by inhibition of outward potassium currents. It is also shown to activate T-type Ca2+ channel and increase gastric emptying, intestinal and colonic contractility. At higher concentrations (100-300uM), reduced amplitude of spontaneous contractions and action potentials is thought to be mediated by inhibition of L-type Ca2+ channels and inward calcium current. Trimebutine mediates a local anesthetic action by acting as a weak agonist at mu opioid receptors.

Drugs used for their effects on the gastrointestinal system, as to control gastric acidity, regulate gastrointestinal motility and water flow, and improve digestion. (See all compounds classified as Gastrointestinal Agents.)|Agents that inhibit the actions of the parasympathetic nervous system. The major group of drugs used therapeutically for this purpose is the MUSCARINIC ANTAGONISTS. (See all compounds classified as Parasympatholytics.)

The free base form or salt form of trimebutine are rapidly absorbed after oral administration, with the peak plasma concentration reached after 1 hour of ingestion. The time to reach peak plasma concentration following a single oral dose of 200mg trimebutine is 0.80 hours.|Renal elimination is predominant while excretion into feces is also observed (5-12%). About 94% of an oral dose of trimebutine is eliminated by the kidneys in the form of various metabolites and less than 2.4% of total ingested drug is recovered as unchanged parent drug in the urine.|Trimebutine is most likely to be accumulated in the stomach and the intestinal walls in highest concentrations. The fetal transfer is reported to be low.

Trimebutine undergoes extensive hepatic first-pass metabolism. Nortrimebutine, or N-monodesmethyltrimebutine, is the main metabolite that retains pharmacological activity on the colon. This metabolite can undergo second N-demethylation to form N-didesmethyltrimebutine. Other main urinary metabolites (2-amino, 2-methylamino or 2-dimethylamino-2-phenylbutan-1-ol) can be formed via hydrolysis of the ester bond of desmethylated metabolites or initial hydrolysis of the ester bond of trimebutine followed by sequential N-demethylation. Trimebutine is also prone to sulphate and/or glucuronic acid conjugation.

The elimination half life is approximately 1 hour following a single oral dose of 2mg/kg, and 2.77 hours following a single oral dose 200 mg.

At high concentrations, trimebutine is shown to inhibit the extracellular Ca2+ influx in the smooth muscle cells through voltage dependent L-type Ca2+ channels and further Ca2+ release from intracellular Ca2+ stores. Trimebutine is suggested to bind to the inactivated state of the calcium channel with high affinity. Reduced calcium influx attenuates membrane depolarization and decrease colon peristalsis. It also inhibits outward K+ currents in response to membrane depolarization of the GI smooth muscle cells at resting conditions through inhibition of delayed rectifier K+ channels and Ca2+ dependent K+ channels, which results in induced muscle contractions. Trimebutine binds to mu opioid receptors with more selectivity compared to delta or kappa opioid receptors but with lower affinity than their natural ligands. Its metabolites (N-monodesmethyl-trimebutine or nor-trimebutine), are also shown to bind to opoid receptors on brain membranes and myenteric synaptosomes.

Debridat