Chemical formula: C₂₁H₂₃NO₄S Molecular mass: 385.48 g/mol PubChem compound: 107751
Racecadotril is a pro-drug that needs to be hydrolysed to its active metabolite thiorphan, which is an inhibitor of enkephalinase, a cell membrane peptidase enzyme located in various tissues, notably the epithelium of the small intestine.
This enzyme contributes both to the digestion of exogenous peptides and to the breakdown of endogenous peptides such as enkephalins.
Racecadotril protects enkephalins from enzymatic degradation thereby prolonging their action at enkephalinergic synapses in the small intestine and reducing hypersecretion.
Racecadotril is a pure intestinal antisecretory active substance. It decreases the intestinal hypersecretion of water and electrolytes induced by the cholera toxin or inflammation, and does not have effects on basal secretory activity. Racecadotril exerts rapid antidiarrhoeal action, without modifying the duration of intestinal transit.
Following oral administration, racecadotril is rapidly absorbed.
The exposure at steady state is comparable with the exposure following a single dose.
In plasma, after an oral dose of 14C-labeled racecadotril, measured exposure of radiocarbon was many orders of magnitude higher than in blood cells and 3-fold higher than in whole blood. Thus, the drug did not bind to blood cells to any significant extent. Radiocarbon distribution in other body tissues was moderate, as indicated by the mean apparent volume of distribution in plasma of 66.4 kg. Ninety percent of the active metabolite of racecadotril (thiorphan=(RS)N(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycin), is bound to plasma proteins, mainly to albumin.
The duration and extent of the effect of racecadotril are dose-dependent. Time to peak plasma enkephalinase inhibition is approximately 2 hours and corresponds to an inhibition of 90% with the dose of 1.5 mg/kg. The duration of plasma enkephalinase inhibition is about 8 hours.
The half-life of racecadotril, measured as plasma enkephalinase inhibition, is approximately 3 hours. Racecadotril is rapidly hydrolysed to thiorphan (RS)N(1-oxo-2-(mercaptomethyl)-3-phenylpropyl) glycin, the active metabolite, which is in turn transformed into inactive metabolites identified as sulfoxyde of Smethylthiorphan, S-methyl thiorphan, 2-methanesulfinylmethyl propionic acid and 2-methylsulfanylmethyl propionic acid, which all were formed at greater than 10% of parent drug systemic exposure.
Additional minor metabolites were also detected and quantified in urine and faeces.
In vitro data indicate that racecadotril/thiorphan and the four major inactive metabolites do not inhibit the major CYP enzymes isoforms 3A4, 2D6, 2C9, 1A2 and 2C19 to an extent that would be clinically relevant. In vitro data indicate that racecadotril/thiorphan and the four major inactive metabolites do not induce the CYP enzymes isoforms (3A family, 2A6, 2B6, 2C9/2C19, 1A family, 2E1) and UGTs conjugating enzymes to an extent that would be clinically relevant.
In the paediatric population, pharmacokinetic results are similar to those of the adult population, reaching Cmax at 2 hours 30 min after administration. There is no accumulation after multiple dose administrated every 8 hours, for 7 days.
Racecadotril is eliminated as active and inactive metabolites. Elimination is mainly via the renal route (81.4%), and to a much lesser extent via the faecal route (around 8%). The pulmonary route is not significant (less than 1% of the dose).
Chronic 4-week toxicity studies in monkeys and dogs, relevant for the duration of treatment in human, do not point out any effect at doses up to 1250 mg/kg/day and 200 mg/kg, respectively corresponding to safety margins of 625 and 62 (vs human). Racecadotril was not immunotoxic in mice given racecadotril for up to 1 month. Longer exposure (1 year) in monkeys showed generalized infections and reduced antibody responses to vaccination at a 500 mg/kg/day dose and no infection/immune depression at 120 mg/kg/day. Similarly in the dog receiving 200 mg/kg/day for 26 weeks some infection/immune parameters were affected. The clinical relevance is unknown see section 4.8.
No mutagenic or clastogenic effect of racecadotril has been found in the standard in vitro and in vivo tests.
Carcinogenicity testing has not been performed with racecadotril as the drug is provided for short-term treatment.
Reproductive and developmental toxicity (fertility and early embryonic development, prenatal and postnatal development including maternal function, embryo-foetal development studies) have not revealed any special effects of racecadotril.
A toxicity study in juvenile rats has not revealed any significant effects of racecadotril up to a dose of 160mg/kg/day which is 35 times higher than the usual paediatric regimen (i.e. 4.5mg/kg/day).
Despite the immature renal function in children below 1 year of age, higher exposure levels are not expected in these individuals
Other preclinical effects (e.g. severe, most likely aplastic anaemia, increased diuresis, ketonuria, diarrhoea,) were observed only at exposures considered sufficiently in excess of maximum human exposure. Their clinical relevance is unknown.
Other safety pharmacology studies did not evidence any deleterious effects of racecadotril on the central nervous system, the cardiovascular and the respiratory functions.
In animals, racecadotril reinforced the effects of butylhyoscine upon bowel transit and on the anticonvulsive effects of phenytoin.
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