Indications
Prucalopride is indicated for the treatment of chronic idiopathic constipation (CIC) in adults. CIC is a prevalent chronic functional gastrointestinal disorder characterized by a range of symptoms, which help confirm diagnosis. Diagnosis is considered when a patient experiences at least two of the following symptoms: straining during more than 25% of bowel movements, lumpy or hard stools in 25% of bowel movements, a sensation of incomplete evacuation in more than 25% of bowel movements, a sensation of anorectal blockage or obstruction in over 25% of bowel movements, the need for manual maneuvers in over 25% of bowel movements, or having fewer than three bowel movements per week.
Pharmacodynamics
Prucalopride has demonstrated a dose-dependent stimulation of contractile activity in animal studies, enhancing activity in the proximal colon while inhibiting the same in the distal colon. Additionally, the drug has been shown to stimulate and intensify giant migratory contractions, which induce the urge to defecate. As a result, prucalopride effectively enhances colonic transit, gastric emptying, and small bowel transit. At supratherapeutic levels, prucalopride interacts with hERG potassium channels and L-type calcium channels. Clinical trials have shown that prucalopride significantly improves spontaneous bowel movements, with a standardized mean difference of approximately 0.5 at a 1 mg dose compared to placebo. These studies also noted marked improvements in colonic transit time and spontaneous complete bowel movements without significant changes in anorectal function. In phase III clinical trials, 86% of participants chose to continue with the open-label study, with 67% reporting more than a one-point improvement in satisfaction. In final approval trials, there was a significant rise in patients achieving more than three complete spontaneous bowel movements per week compared to placebo.
Absorption
Prucalopride is well absorbed, reaching peak plasma concentration of 3.79 ng/ml, with a tmax of 2.77 hours following initial administration. It has an AUC of 96.5 mn.h/ml, and its bioavailability exceeds 90%. Importantly, the bioavailability of prucalopride is not affected by concomitant food intake.
Metabolism
Prucalopride undergoes minimal metabolism in the body, showing no interaction with cytochrome P450 enzymes or P-glycoprotein. Only 6% of the administered dose is metabolized, with the remaining 94% excreted as the unchanged drug. Studies have identified eight metabolites, with R107504 being the primary metabolite formed via O-demethylation and subsequent oxidation to a carboxylic acid.
Mechanism of Action
Prucalopride functions as a selective agonist of 5-HT4 receptors, distinctively lacking interaction with hERG channels or 5-HT1 receptors, thereby substantially reducing the cardiovascular risks associated with other similar medications. These 5-HT4 receptors are predominantly located throughout the gastrointestinal tract, including in smooth muscle cells, enterochromaffin cells, and the myenteric plexus. Activation of these receptors triggers the release of acetylcholine, the primary excitatory neurotransmitter within the gastrointestinal system. By specifically targeting 5-HT4 receptors, prucalopride enhances gastrointestinal motility. It achieves this by stimulating the release of acetylcholine, which induces contraction of the colonic muscle layer and relaxation of the circular muscle layer, thereby facilitating the propulsion of luminal contents.
