Trimebutine

191.12 Ų [M+Na]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；177.75 Ų [M+H-H2O]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；197.43 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]；193.19 Ų [M+K]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

This chemical does not meet GHS hazard criteria for 61.5% (8 of 13) of all reports.

Warning

H302 (23.1%): Harmful if swallowed [Warning Acute toxicity, oral]；H312 (30.8%): Harmful in contact with skin [Warning Acute toxicity, dermal]；H332 (30.8%): Harmful if inhaled [Warning Acute toxicity, inhalation]；H413 (15.4%): May cause long lasting harmful effects to aquatic life [Hazardous to the aquatic environment, long-term hazard]

P261, P264, P270, P271, P273, P280, P301+P317, P302+P352, P304+P340, P317, P321, P330, P362+P364, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 13 reports by companies from 5 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.；Reported as not meeting GHS hazard criteria per 8 of 13 reports by companies.；There are 4 notifications provided by 5 of 13 reports by companies with hazard statement code(s).；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

Chemical: Benzoic acid, 3,4,5-trimethoxy-, 2-(dimethylamino)-2-phenylbutyl ester

Status: Active Update: 23-05-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/25765

Drug-Induced Liver Injury Severity and Toxicity (DILIst)

Trimebutine

DILI Positive

DOI:10.1016/j.drudis.2019.09.022

Chemical: Benzoic acid, 3,4,5-trimethoxy-, 2-(dimethylamino)-2-phenylbutyl ester

Status: Active Update: 23-05-2018 https://echa.europa.eu/registration-dossier/-/registered-dossier/25765

A - Alimentary tract and metabolism；A03 - Drugs for functional gastrointestinal disorders；A03A - Drugs for functional gastrointestinal disorders；A03AA - Synthetic anticholinergics, esters with tertiary amino group；A03AA05 - Trimebutine

QA - Alimentary tract and metabolism；QA03 - Drugs for functional gastrointestinal disorders；QA03A - Drugs for functional gastrointestinal disorders；QA03AA - Synthetic anticholinergics, esters with tertiary amino group；QA03AA05 - Trimebutine

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.

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.

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.

Drugs used for their effects on the gastrointestinal system, as to control gastric acidity, regulate gastrointestinal motility and water flow, and improve digestion.

Agents that inhibit the actions of the parasympathetic nervous system. The major group of drugs used therapeutically for this purpose is the MUSCARINIC ANTAGONISTS.

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.