Duspatalin Retard Mechanism of Action

Pharmacotherapeutic group: synthetic anticholinergics, esters with tertiary amino group. ATC code: A03AA04.
Pharmacology: Pharmacodynamics: Mechanism of action and pharmacodynamic effects: Mebeverine is a musculotropic spasmolytic agent with a direct effect on the smooth muscles of the gastro-intestinal tract without affecting the normal intestinal motility. Because this effect is not brought about via the autonomic nervous system, the typical anticholinergic adverse effects do not occur.
Pharmacokinetics: Absorption: Mebeverine is quickly and fully absorbed after oral administration of tablets. The formulation with controlled release allows for a twice daily dosage scheme.
Distribution: No significant accumulation occurs after multidosage use.
Biotransformation: Mebeverine hydrochloride is mainly metabolized by esterases, which first split the ester compounds into veratric acid and mebeverine alcohol. The main metabolite in plasma is DMAC (demethylated carboxylic acid). The steady state elimination half life of DMAC is 5.77 hours. During multidosage use (200 mg twice daily) the C_max of DMAC is 804 ng/ml and the t_max is about 3 hours. The relative biological availability of the controlled-release capsule appears to be optimal with an average ratio of 97%.
Elimination: Mebeverine is not excreted as such but excreted fully metabolized; the metabolites are excreted almost completely. Veratric acid is excreted into the urine; mebeverine alcohol is also excreted into the urine, partly as the corresponding carboxylic acid (MAC) and partly as the demethylated carboxylic acid (DMAC).
Paediatric population: No clinical investigations in children have taken place with any form of mebeverine.
Toxicology: Preclinical safety data: Effects in repeat-dose studies after oral and parenteral doses were indicative of central nervous involvement with behavioral excitation, mainly tremor and convulsions. In the dog, the most sensitive species, these effects were seen at oral doses equivalent to 3 times the maximum recommended clinical dose of 400 mg/day based on body surface area (mg/m²) comparisons.
The reproductive toxicity of mebeverine was not sufficiently investigated in animal studies. There was no indication of teratogenic potential in rats and rabbits. However, embryotoxic effects (reduction in litter size, increased incidence of resorption) were noticed in rats at doses equivalent to twice the maximum daily clinical dose. This effect was not observed in rabbits. No effects on male or female fertility were noted in rats at doses equivalent to the maximum clinical dose.
In conventional in vitro and in vivo genotoxicity tests mebeverine was devoid of genotoxic effects. No carcinogenicity studies have been performed.