Chemistry:Prucalopride

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Short description: Drug used to treat chronic constipation
Prucalopride
Prucalopride.svg
Clinical data
Trade namesResolor, Resotran, Motegrity
Other namesR-093877, R-108512
AHFS/Drugs.comMonograph
MedlinePlusa619011
License data
Pregnancy
category
  • AU: B1
Routes of
administration		By mouth
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only) [1]
  • UK: POM (Prescription only)
  • US: ℞-only
  • EU: Rx-only
  • In general: ℞ (Prescription only)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC18H26ClN3O3
Molar mass367.87 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Prucalopride, sold under brand names Resolor and Motegrity among others, is a medication acting as a selective, high affinity 5-HT4 receptor agonist[2] which targets the impaired motility associated with chronic constipation, thus normalizing bowel movements.[3][4][5][6][7][8] Prucalopride was approved for medical use in the European Union in 2009,[9] in Canada in 2011,[10] in Israel in 2014,[11] and in the United States in December 2018.[12] The drug has also been tested for the treatment of chronic intestinal pseudo-obstruction.[13][14]

Medical uses

The primary measure of efficacy in the clinical trials is three or more spontaneous complete bowel movements per week; a secondary measure is an increase of at least one complete spontaneous bowel movement per week.[8][15][16] Further measures are improvements in PAC-QOL[17] (a quality of life measure) and PAC-SYM[18] (a range of stool, abdominal, and rectal symptoms associated with chronic constipation). Infrequent bowel movements, bloating, straining, abdominal pain, and defecation urge with inability to evacuate can be severe symptoms, significantly affecting quality of life.[19][20][21][22][23]

In three large clinical trials, 12 weeks of treatment with prucalopride 2 and 4 mg/day resulted in a significantly higher proportion of patients reaching the primary efficacy endpoint of an average of ≥3 spontaneous complete bowel movements than with placebo.[8][15][16] There was also significantly improved bowel habit and associated symptoms, patient satisfaction with bowel habit and treatment, and HR-QOL in patients with severe chronic constipation, including those who did not experience adequate relief with prior therapies (>80% of the trial participants).[8][15][16] The improvement in patient satisfaction with bowel habit and treatment was maintained during treatment for up to 24 months; prucalopride therapy was generally well tolerated.[24][25]

Small clinical trials suggested that prucalopride administration results in the 5-HT4 receptor agonism-associated memory enhancing in healthy participants improving their ability to recall and increasing neural activation in the hippocampus and functionally related areas.[26][27]

Contraindications

Prucalopride is contraindicated where there is hypersensitivity to the active substance or to any of the excipients, renal impairment requiring dialysis, intestinal perforation or obstruction due to structural or functional disorder of the gut wall, obstructive ileus, severe inflammatory conditions of the intestinal tract, such as Crohn's disease, and ulcerative colitis and toxic megacolon/megarectum.[28]

Side effects

Prucalopride has been given orally to ~2700 patients with chronic constipation in controlled clinical trials. The most frequently reported side effects are headache and gastrointestinal symptoms (abdominal pain, nausea or diarrhea). Such reactions occur predominantly at the start of therapy and usually disappear within a few days with continued treatment.[28]

Mechanism of action

Prucalopride, a first in class dihydro-benzofuran-carboxamide, is a selective, high affinity serotonin (5-HT4) receptor agonist with enterokinetic activities.[28] Prucalopride alters colonic motility patterns via serotonin 5-HT4 receptor stimulation: it stimulates colonic mass movements, which provide the main propulsive force for defecation.

The observed effects are exerted via highly selective action on 5-HT4 receptors:[28] prucalopride has >150-fold higher affinity for 5-HT4 receptors than for other receptors.[2][29] Prucalopride differs from other 5-HT4 agonists such as tegaserod and cisapride, which at therapeutic concentrations also interact with other receptors (5-HT1B/D and the cardiac human ether-a-go-go K+ or hERG channel respectively) and this may account for the adverse cardiovascular events that have resulted in the restricted availability of these drugs.[29] Clinical trials evaluating the effect of prucalopride on QT interval and related adverse events have not demonstrated significant differences compared with placebo.[28]

Pharmacokinetics

Prucalopride is rapidly absorbed (Cmax attained 2–3 hours after single 2 mg oral dose) and is extensively distributed. Metabolism is not the major route of elimination. In vitro, human liver metabolism is very slow and only minor amounts of metabolites are found. A large fraction of the active substance is excreted unchanged (about 60% of the administered dose in urine and at least 6% in feces). Renal excretion of unchanged prucalopride involves both passive filtration and active secretion. Plasma clearance averages 317 ml/min, terminal half-life is 24–30 hours,[30] and steady-state is reached within 3–4 days. On once daily treatment with 2 mg prucalopride, steady-state plasma concentrations fluctuate between trough and peak values of 2.5 and 7 ng/ml, respectively.[28]

In vitro data indicate that prucalopride has a low interaction potential, and therapeutic concentrations of prucalopride are not expected to affect the CYP-mediated metabolism of co-medicated medicinal products.[28]

Approval

In the European Economic Area, prucalopride was originally approved for the symptomatic treatment of chronic constipation in women in whom laxatives fail to provide adequate relief.[28] Subsequently, it has been approved by the European Commission for use in adults – that is, including male patients – for the same indication.[31]

References

  1. ↑ "Prucalopride succinate (MedTAS Pty Ltd)". 7 October 2022. https://www.tga.gov.au/resources/prescription-medicines-registrations/prucalopride-succinate-medtas-pty-ltd. 
  2. ↑ 2.0 2.1 "The in vitro pharmacological profile of prucalopride, a novel enterokinetic compound". European Journal of Pharmacology 423 (1): 71–83. June 2001. doi:10.1016/S0014-2999(01)01087-1. PMID 11438309. 
  3. ↑ Clinical trial number NCT00793247 for "Efficacy Study of Prucalopride to Treat Chronic Intestinal Pseudo-Obstruction (CIP)" at ClinicalTrials.gov
  4. ↑ "Randomised clinical trial: the efficacy of prucalopride in patients with chronic intestinal pseudo-obstruction--a double-blind, placebo-controlled, cross-over, multiple n = 1 study". Alimentary Pharmacology & Therapeutics 35 (1): 48–55. January 2012. doi:10.1111/j.1365-2036.2011.04907.x. PMID 22061077. 
  5. ↑ "The successful treatment of acute refractory pseudo-obstruction with prucalopride". Colorectal Disease 14 (8): e508. August 2012. doi:10.1111/j.1463-1318.2011.02929.x. PMID 22212130. 
  6. ↑ "Selective stimulation of colonic transit by the benzofuran 5HT4 agonist, prucalopride, in healthy humans". Gut 44 (5): 682–6. May 1999. doi:10.1136/gut.44.5.682. PMID 10205205. 
  7. ↑ "Prucalopride accelerates gastrointestinal and colonic transit in patients with constipation without a rectal evacuation disorder". Gastroenterology 120 (2): 354–60. February 2001. doi:10.1053/gast.2001.21166. PMID 11159875. 
  8. ↑ 8.0 8.1 8.2 8.3 "Prucalopride (Resolor) in the treatment of severe chronic constipation in patients dissatisfied with laxatives". Gut 58 (3): 357–65. March 2009. doi:10.1136/gut.2008.162404. PMID 18987031. 
  9. ↑ "Resolor EPAR". https://www.ema.europa.eu/en/medicines/human/EPAR/resolor. 
  10. ↑ "Health Canada, Notice of Decision for Resotran". http://www.hc-sc.gc.ca/dhp-mps/prodpharma/sbd-smd/drug-med/sbd_smd_2012_resotran_141157-eng.php#a2. 
  11. ↑ "Digestive Remedies in Israel". http://www.euromonitor.com/digestive-remedies-in-israel/report. 
  12. ↑ "Drug Approval Package: Motegrity (prucalopride)". 28 December 2018. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210166Orig1s000TOC.cfm. 
  13. ↑ "Effects of the enterokinetic prucalopride (R093877) on colonic motility in fasted dogs". Neurogastroenterology and Motility 13 (5): 465–72. October 2001. doi:10.1046/j.1365-2982.2001.00280.x. PMID 11696108. 
  14. ↑ "Prucalopride for chronic intestinal pseudo-obstruction". Alimentary Pharmacology & Therapeutics 35 (3): 398–9. February 2012. doi:10.1111/j.1365-2036.2011.04947.x. PMID 22221087. 
  15. ↑ 15.0 15.1 15.2 "A placebo-controlled trial of prucalopride for severe chronic constipation". The New England Journal of Medicine 358 (22): 2344–54. May 2008. doi:10.1056/NEJMoa0800670. PMID 18509121. 
  16. ↑ 16.0 16.1 16.2 "Clinical trial: the efficacy, impact on quality of life, and safety and tolerability of prucalopride in severe chronic constipation--a 12-week, randomized, double-blind, placebo-controlled study". Alimentary Pharmacology & Therapeutics 29 (3): 315–28. February 2009. doi:10.1111/j.1365-2036.2008.03884.x. PMID 19035970. 
  17. ↑ "Development and validation of the Patient Assessment of Constipation Quality of Life questionnaire". Scandinavian Journal of Gastroenterology 40 (5): 540–51. May 2005. doi:10.1080/00365520510012208. PMID 16036506. 
  18. ↑ "Psychometric validation of a constipation symptom assessment questionnaire". Scandinavian Journal of Gastroenterology 34 (9): 870–7. September 1999. doi:10.1080/003655299750025327. PMID 10522604. 
  19. ↑ "Chronic constipation: a survey of the patient perspective". Alimentary Pharmacology & Therapeutics 25 (5): 599–608. March 2007. doi:10.1111/j.1365-2036.2006.03238.x. PMID 17305761. 
  20. ↑ "Symptoms in chronic constipation". Diseases of the Colon and Rectum 40 (8): 902–6. August 1997. doi:10.1007/BF02051196. PMID 9269805. 
  21. ↑ "Gender differences in self-reported constipation characteristics, symptoms, and bowel and dietary habits among patients attending a specialty clinic for constipation". Gender Medicine 6 (1): 259–71. April 2009. doi:10.1016/j.genm.2009.04.007. PMID 19467522. 
  22. ↑ "An epidemiological survey of constipation in canada: definitions, rates, demographics, and predictors of health care seeking". The American Journal of Gastroenterology 96 (11): 3130–7. November 2001. doi:10.1111/j.1572-0241.2001.05259.x. PMID 11721760. 
  23. ↑ "The burden of constipation on quality of life: results of a multinational survey". Alimentary Pharmacology & Therapeutics 26 (2): 227–36. July 2007. doi:10.1111/j.1365-2036.2007.03376.x. PMID 17593068. 
  24. ↑ "Long-term follow-up of safety and satisfaction with bowel function in response to oral prucalopride in patients with chronic constipation [Abstract]". Gastroenterology 136 (Suppl 1): 160. 2009. doi:10.1016/s0016-5085(09)60143-8. 
  25. ↑ "Long-term follow-up study of oral prucalopride (Resolor) administered to patients with chronic constipation [Abstract T1400]". Gastroenterology 134 (4 (suppl 1)): A547. 2008. doi:10.1016/s0016-5085(08)62554-8. 
  26. ↑ "A role for 5-HT4 receptors in human learning and memory". Psychological Medicine 50 (16): 2722–2730. December 2020. doi:10.1017/S0033291719002836. PMID 31615585. 
  27. ↑ "Déjà-vu? Neural and behavioural effects of the 5-HT4 receptor agonist, prucalopride, in a hippocampal-dependent memory task". Translational Psychiatry 11 (1): 497. October 2021. doi:10.1038/s41398-021-01568-4. PMID 34602607. 
  28. ↑ 28.0 28.1 28.2 28.3 28.4 28.5 28.6 28.7 SmPC. Summary of product characteristics Resolor (prucalopride) October, 2009: 1-9.
  29. ↑ 29.0 29.1 "5-HT4 receptor agonists: similar but not the same". Neurogastroenterology and Motility 20 (2): 99–112. February 2008. doi:10.1111/j.1365-2982.2007.01059.x. PMID 18199093. 
  30. ↑ "Prucalopride". Drugs 69 (17): 2463–76. 2009. doi:10.2165/11204000-000000000-00000. PMID 19911858. 
  31. ↑ "Shire Receives European Approval to Use Resolor (prucalopride) in Men for the Symptomatic Treatment of Chronic Constipation". https://www.shire.com/newsroom/2015/june/resolor-eu-male-indication-press-release. 



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