Trimebutine

Trimebutine is a noncompetitive spasmolytic agent. It possesses moderate opiate receptor affinity and has a marked antiserotonin activity especially on ‘M’ receptors. It induces regulation of spontaneous activity and increases synchronization between electrophysiological spikes and contractions in isolated guinea pig taenia coli and ileum. However, it does not alter normal motility, but regulates abnormal intestinal activity.

Metabolic studies in rat, dog and man showed that C¹⁴-trimebutine maleate or its free base is rapidly absorbed after oral administration. Peak plasma concentrations of radioactivity were observed within one hour in man and rat and within two to four hours in the dog.

Plasma radioactivity in man indicated a kinetic model with central and peripheral compartments and a mean distribution half-life of 0.66 hour. Tissue distribution studies showed high concentration of the radiolabelled drug in the stomach and the intestinal walls of rat and in the major organs of metabolism and excretion in mice. Placental transfer without teratogenic effect was observed in the rat. Protein-binding was less than 5% in vivo (rat plasma) and in vitro (bovine serum albumin).

Urine was the main route of elimination in all species while a small percentage (5-12%) of radioactivity was detected in the faeces. The plasma half-life of trimebutine was short, but the elimination half-life of radioactivity was approximately 10-12 hours in man and rat. In the rat, an entero-hepatic circulation was also demonstrated.

Extensive metabolism of the parent compound was indicated since less than 2.4% of the urinary radioactivity was found as unchanged drug in all species. The livers of rat and dog appeared to be the major site of hydrolysis of the ester and also capable of a “first pass” metabolism.

The main urinary metabolites in all species were 2-amino (I) or 2-methylamino (II) or 2-dimethylamino-2-phenylbutan-1-ol (III). These three metabolites plus mono-N-desmethyl trimebutine (IV) were also shown in plasma; the major component was III in rat and dog and IV in man. Sulphate and/or glucuronic acid conjugation was also shown to play an important role in metabolism.