Duspatalin Mechanism of Action

Pharmacotherapeutic group: Synthetic anticholinergics, esters with tertiary amino group. ATC-Code: A03AA04.
Pharmacology: Pharmacodynamics: Mechanism of action: Mebeverine is a musculotropic antispasmodic with a direct effect on the smooth muscle of the gastrointestinal tract, without affecting normal gut motility.
The exact mechanism of action is not known, but multiple mechanisms, such as a decrease in ion channel permeabilities, blockade of noradrenaline reuptake, a local anesthetic effect, changes in water absorption might contribute to the local effect of mebeverine on the gastrointestinal tract. Via these mechanisms mebeverine has antispasmodic effects leading to normalization of gut motility without exerting a permanent relaxation of smooth muscle cells in the gastrointestinal tract (so called hypotonia). Systemic side-effects as seen with typical anti-cholinergics are absent.
Clinical efficacy and safety: The clinical efficacy and safety of different formulations of mebeverine was evaluated in more than 1500 patients. Considerable improvements in the predominant symptomatology of irritable bowel syndrome (e.g. abdominal pain, stool characteristics) were generally observed in reference or baseline-controlled clinical studies.
Mebeverine were generally safe and well tolerated in the recommended dose regimen.
Paediatric population: Clinical trials with the tablet or capsule formulations have been performed in adults only.
The dosing schedule for the tablet formulation was calculated based on the consistent safety and favourable tolerability of mebeverine.
Pharmacokinetics: Absorption: Mebeverine is rapidly and completely absorbed after oral administration of tablets.
Distribution: No significant accumulation occurs after multiple doses.
Biotransformation: Mebeverine hydrochloride is mainly metabolized by esterases, which split the ester bonds 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 2.45 h. During multiple dosing Cmax of DMAC for the coated tablets with 135 mg is 1670 ng/ml and tmax is 1 h.
Elimination: Mebeverine is not excreted as such, but metabolized completely; the metabolites are excreted nearly 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 pharmacokinetic studies have been conducted in children with any formulation of mebeverine.
Toxicology: Preclinical Safety Data: Effects in repeat-dose studies after oral and parenteral doses were indicative of central nervous involvement excitation with behavioral, 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 400mg/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.