Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies
Background: Prucalopride is a selective serotonin type 4 (5-HT4) receptor agonist indicated for treatment of chronic idiopathic constipation (CIC) in adults (2 mg orally, daily). 5-HT4 receptors are present in the central nervous system; therefore, non-clinical and clinical assessments were performe...
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| Format: | Article |
| Language: | English |
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BioExcel Publishing Ltd
2023-02-01
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| Series: | Drugs in Context |
| Subjects: | |
| Online Access: | https://www.drugsincontext.com/tissue-distribution-and-abuse-potential-of-prucalopride-findings-from-non-clinical-and-clinical-studies/ |
| _version_ | 1797894139394654208 |
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| author | Katayoun Derakhchan Zhen Lou Hong Wang Robert Baughman |
| author_facet | Katayoun Derakhchan Zhen Lou Hong Wang Robert Baughman |
| author_sort | Katayoun Derakhchan |
| collection | DOAJ |
| description | Background: Prucalopride is a selective serotonin type 4 (5-HT4) receptor agonist indicated for treatment of chronic idiopathic constipation (CIC) in adults (2 mg orally, daily). 5-HT4 receptors are present in the central nervous system; therefore, non-clinical and clinical assessments were performed to evaluate the tissue distribution and abuse potential of prucalopride.
Methods: In vitro receptor-ligand binding studies were performed to assess the affinity of prucalopride (≤1 mM) for peptide receptors, ion channels, monoamine neurotransmitters and 5-HT receptors. The tissue distribution of 14C-prucalopride (5 mg base-equivalent/kg) was investigated in rats. Behavioural assessments in mice, rats and dogs after treatment with single or repeated (up to 24 months) subcutaneous or oral doses of prucalopride (0.02–640 mg/kg across species) were performed. Treatment-emergent adverse events possibly indicative of abuse potential during prucalopride CIC clinical trials were evaluated.
Results: Prucalopride showed no appreciable affinity for the receptors and ion channels investigated; its affinity (at ≤100 μM) for other 5-HT receptors was 150–10,000 times lower than that for the 5-HT4 receptor. In rats, <0.1% of the administered dose was found in the brain and concentrations were below the limit of detection within 24 hours. At supratherapeutic doses (≥20 mg/kg), mice and rats exhibited palpebral ptosis, and dogs exhibited salivation, eyelid tremors, decubitis, pedalling movements and sedation. All clinical treatment-emergent adverse events, possibly indicative of abuse potential, except dizziness, occurred in <1% of patients treated with prucalopride or placebo.
Conclusion: This series of non-clinical and clinical studies suggest low abuse potential for prucalopride. |
| first_indexed | 2024-04-10T07:05:18Z |
| format | Article |
| id | doaj.art-9c9bd82391d14b6ea56dd43cffa25c06 |
| institution | Directory Open Access Journal |
| issn | 1740-4398 |
| language | English |
| last_indexed | 2024-04-10T07:05:18Z |
| publishDate | 2023-02-01 |
| publisher | BioExcel Publishing Ltd |
| record_format | Article |
| series | Drugs in Context |
| spelling | doaj.art-9c9bd82391d14b6ea56dd43cffa25c062023-02-27T10:30:16ZengBioExcel Publishing LtdDrugs in Context1740-43982023-02-011211610.7573/dic.2022-6-1Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studiesKatayoun DerakhchanZhen LouHong WangRobert BaughmanBackground: Prucalopride is a selective serotonin type 4 (5-HT4) receptor agonist indicated for treatment of chronic idiopathic constipation (CIC) in adults (2 mg orally, daily). 5-HT4 receptors are present in the central nervous system; therefore, non-clinical and clinical assessments were performed to evaluate the tissue distribution and abuse potential of prucalopride. Methods: In vitro receptor-ligand binding studies were performed to assess the affinity of prucalopride (≤1 mM) for peptide receptors, ion channels, monoamine neurotransmitters and 5-HT receptors. The tissue distribution of 14C-prucalopride (5 mg base-equivalent/kg) was investigated in rats. Behavioural assessments in mice, rats and dogs after treatment with single or repeated (up to 24 months) subcutaneous or oral doses of prucalopride (0.02–640 mg/kg across species) were performed. Treatment-emergent adverse events possibly indicative of abuse potential during prucalopride CIC clinical trials were evaluated. Results: Prucalopride showed no appreciable affinity for the receptors and ion channels investigated; its affinity (at ≤100 μM) for other 5-HT receptors was 150–10,000 times lower than that for the 5-HT4 receptor. In rats, <0.1% of the administered dose was found in the brain and concentrations were below the limit of detection within 24 hours. At supratherapeutic doses (≥20 mg/kg), mice and rats exhibited palpebral ptosis, and dogs exhibited salivation, eyelid tremors, decubitis, pedalling movements and sedation. All clinical treatment-emergent adverse events, possibly indicative of abuse potential, except dizziness, occurred in <1% of patients treated with prucalopride or placebo. Conclusion: This series of non-clinical and clinical studies suggest low abuse potential for prucalopride.https://www.drugsincontext.com/tissue-distribution-and-abuse-potential-of-prucalopride-findings-from-non-clinical-and-clinical-studies/central nervous systemconstipationdrug abusedrug toxicitypharmacokineticspharmacologyprucalopridetoxicology |
| spellingShingle | Katayoun Derakhchan Zhen Lou Hong Wang Robert Baughman Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies Drugs in Context central nervous system constipation drug abuse drug toxicity pharmacokinetics pharmacology prucalopride toxicology |
| title | Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies |
| title_full | Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies |
| title_fullStr | Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies |
| title_full_unstemmed | Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies |
| title_short | Tissue distribution and abuse potential of prucalopride: findings from non-clinical and clinical studies |
| title_sort | tissue distribution and abuse potential of prucalopride findings from non clinical and clinical studies |
| topic | central nervous system constipation drug abuse drug toxicity pharmacokinetics pharmacology prucalopride toxicology |
| url | https://www.drugsincontext.com/tissue-distribution-and-abuse-potential-of-prucalopride-findings-from-non-clinical-and-clinical-studies/ |
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