Racecadotril

Racecadotril is a prodrug that hydrolyzes to an active metabolite, tiforvan, which is an enkephalinase inhibitor, a surface peptidase (located on the cell membrane) located in various tissues, especially in the epithelium of the small intestine. This enzyme is simultaneously responsible for the hydrolysis of exogenous peptides and the cleavage of endogenous peptides, such as enkephalins. As a result, racecadotril protects endogenous enkephalins, which exhibit physiological activity at the level of the digestive tract, prolonging their antisecretory action.
Racecadotril is an intestinal antisecretory agent. It reduces intestinal hypersecretion of water and electrolytes caused by cholera enterotoxin or inflammation, and does not affect the basal secretion of the intestine.
Racecadotril has a rapid antidiarrheal effect, without changing the time of passage of intestinal contents through the intestines.
Racecadotril does not cause bloating.
In clinical trials, the incidence of secondary constipation when taking racecadotril was comparable to placebo.
Pharmacokinetics
Suction. After ingestion, racecadotril is rapidly absorbed. The time before the start of inhibition of plasma enkephalinase is 30 minutes. Meal does not affect the bioavailability of racecadotril, but after a meal, the activity of the drug is delayed by about one and a half hours.
Distribution. In the blood plasma after the application of racecadotril, labeled with a 14C radioactive isotope, the content of radiocarbon was many times higher than in blood cells, and 3 times higher than in whole blood. Thus, the drug is slightly associated with blood cells. Radiocarbon is moderately distributed in other tissues of the body, as evidenced by its apparent plasma Vd - 66.4 kg.
90% of the active metabolite of racecadotril (tiorfan) ((RS) -N (1-oxo-2- (mercaptomethyl) -3-phenylpropyl) glycine) binds to plasma proteins, mainly albumin.
The pharmacokinetic properties of racecadotril do not change as a result of receiving repeated doses, as well as when prescribed to elderly patients.
When receiving racecadotril at a dose of 100 mg, the time of peak inhibition of plasma enkephalinase is approximately 2 hours and corresponds to 75% inhibition. The duration and effectiveness of the action of racecadotril depend on the dose of the drug. In adults, the time to peak inhibition of plasma enkephalinase is approximately 2 hours and corresponds to 75% inhibition at a dose of 100 mg. The time of inhibition of plasma enkephalinase is approximately 8 hours.
Metabolism. Biological T1 / 2 racecadotril, measured as the time of plasma enkephalinase inhibition, is approximately 3 h.
Racecadotril is rapidly hydrolyzed to thiorfan, an active metabolite that, in turn, is transformed into inactive metabolites. Reception of repeated doses of racecadotril does not lead to its accumulation in the body. Data obtained from in vitro studies indicate that racecadotril / thiorfan and 4 major inactive metabolites do not inhibit CYP isoenzymes (3A4, 2D6, 2C9, 1F2, and 2C19) to a degree that may be clinically significant.
Data obtained from in vitro studies indicate that racecadadril / thiorphan and 4 major inactive metabolites do not induce CYP isoenzymes (3A, 2A6, 2B6, 2C9 / 2C19, 1A, 2E1) and UDP-HT to the extent that can be clinically meaningful .
Racecadotril does not affect the protein binding of active substances such as tolbutamide, warfarin, niflumic acid, digoxin, or phenytoin.
In patients with hepatic insufficiency (Child-Pugh class B), the kinetic profile of the active metabolite of racecadotril showed similar Tmax and T1 / 2 and lower Cmax values ​​in the blood (−65%) and AUC (−29%) compared to these indicators in healthy people.
In patients with severe renal insufficiency (Cl creatinine 11–39 ml / min), the kinetic profile of the active metabolite of racecadotril showed a lower Cmax (−49%) and higher AUC (+ 16%) and T1 / 2 rates compared with healthy volunteers (Cl creatinine> 70 ml / min). Cmax is reached 2 hours 30 minutes after application.
There was no cumulation with repeated use of the drug every 8 hours for 7 days.
Derivation. Racecadotril is eliminated from the body in the form of active and inactive metabolites, mainly through the kidneys, and much less with feces. Excretion through the lungs is negligible.