Evidence of lowest brain penetration of an antiemetic drug, metopimazine, compared to domperidone, metoclopramide and chlorpromazine, using an in vitro model of the blood–brain barrier

Jolliet, Pascale; Nion, Stéphane; Allain-Veyrac, Gwenaëlle; Tilloy-Fenart, Laurence; Vanuxeem, Dorothée; Bérézowski, Vincent; Cecchelli, Roméo

doi:10.1016/j.phrs.2006.12.004

Cited by 46 publications

(37 citation statements)

References 17 publications

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“…Under these assay conditions, Compound-1 is significantly less permeable into the brain tissue than theophyllin, which is known as a less permeable xanthine analog. 24 On the other hand, SR141716A showed high CL apparent,uptake comparable to metoclopramide or quinine, agents known to be permeable to the BBB. 25 These results mean that Compound-1 cannot reach the brain tissues as efficiently as SR141716A.…”

Section: Discussionmentioning

confidence: 95%

Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control

et al. 2009

Int J Obes

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Objective: To investigate whether drugs targeting peripheral cannabinoid-1 (CB1) receptor ameliorate adiposity comparable to central CB1-receptor antagonist or not. Measurements: Receptor binding assay and functional assay in vitro. Pharmacokinetic parameters in mice, brain uptake clearance of compounds in rats and antagonism on the CB1-agonist-induced hypothermia in mice. Diet consumption, body weight changes, hepatic gene expression of sterol-regulatory element-binding protein-1 (SREBP-1) and plasma/tissue concentrations of compounds in HF diet-induced obese (HF-DIO) mice after acute and chronic treatment. Results: Compound-1, an SR141716A derivative, is a peripheral CB1-receptor-selective antagonist that is 10 times less potent than SR141716A in in vitro evaluations. Although the plasma concentrations of Compound-1 are five times higher than those of SR141716A, its potency is still 10 times lower than that of SR141716A in reducing the consumption of normal or HF diet by mice. Through evaluations of brain uptake and the effect on CB1-agonist-induced hypothermia, it was verified that the bloodbrain barrier (BBB) penetration of Compound-1 is much lower than that of SR141716A. In HF-DIO mice, chronic treatment by Compound-1 showed dose-dependent antiobesity activities, while its brain distribution was very low as compared with that of SR141716A. Compound-1's effective doses for antiobesity activity were just over 30 mg kg À1 . However, Compound-1 completely suppressed the elevated hepatic SREBP-1 expression even at 10 mg kg À1 . Conclusion: These results suggest that (1) central CB1 receptors mediate anorectic response of CB1-receptor antagonists and (2) peripheral modulations, including SREBP-1 expression, are not major mechanisms in the antiobesity effects of CB1-receptor antagonists.

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Section: Discussionmentioning

confidence: 95%

Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control

et al. 2009

Int J Obes

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“…The D1 receptor group is found in the nigrostriatal pathway, and the D2 receptor group is located in the striatopallidal projection; these neuronal pathways regulate the activity in the basal ganglia neuronal output and control voluntary body movements. Metoclopramide crosses the blood‐brain barrier and inhibits D2 group receptor‐mediated activity, resulting in imbalance between the nigrostriatal and striatopallidal pathways, which in turn may lead to extrapyramidal movement disorders. The spectrum of involuntary extrapyramidal movements includes acute dystonia that can appear within some hours after drug administration, as well as parkinsonism and akathisia with bodily unrest and constant body movements.…”

Section: Pharmacodynamic Linkage To Involuntary Movementsmentioning

confidence: 99%

Gastroparesis, metoclopramide, and tardive dyskinesia: Risk revisited

Al‐Saffar

Lennernäs

Hellström

2019

Neurogastroenterology Motil

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Background Metoclopramide is primarily a dopamine receptor antagonist, with 5HT3 receptor antagonist and 5HT4 receptor agonist activity, and used as an antiemetic and gastroprokinetic since almost 50 years. Regulatory authorities issued restrictions and recommendations regarding long‐term use of the drug at oral doses exceeding 10 mg 3‐4 times daily because of the risk for development of tardive dyskinesia. The aim of our study was to review mechanism(s) of action and pharmacokinetic‐pharmacodynamic properties of metoclopramide, as well as the risk of metoclopramide‐induced tardive dyskinesia, factors that may change drug exposure in humans, and to summarize the clinical context for appropriate use of the drug. Methods A PubMed, Google Scholar, and Cross Reference search was done using the key words and combined searches: drug‐drug interaction, gastroparesis, metoclopramide, natural history, pharmacokinetics, pharmacodynamics, drug‐drug interaction, outcome, risk factors, tardive dyskinesia. Key results Data show that the risk of tardive dyskinesia from metoclopramide is low, in the range of 0.1% per 1000 patient years. This is far below a previously estimated 1%‐10% risk suggested in treatment guidelines by regulatory authorities. High‐risk groups are elderly females, diabetics, patients with liver or kidney failure, and patients with concomitant antipsychotic drug therapy, which reduces the threshold for neurological complications. Conclusions & Inferences The risk of tardive dyskinesia due to metoclopramide is far below approximated numbers in treatment guidelines. This risk and the influence of known risk factors should be considered when starting a course of metoclopramide for treatment of gastroparesis.

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“…DOM is a peripheral, dopamine competitive receptor antagonist, that exerts antiemetic effects in various species (Osinski et al, 2005). DOM does not readily cross the blood-brain barrier and is known to cause less central side-effects than alternative anti-emetic treatments (i.e., metoclopramide; Jolliet et al, 2007). Specifically, extremely large doses of DOM are required to obtain central effects (Wauquier, Niemegeers, & Janssen, 1981).…”

Section: Developmental Psychobiologymentioning

confidence: 99%

Domperidone interferes with conditioned disgust reactions but not taste avoidance evoked by a LiCl‐paired taste in infant rats

Pautassi¹,

Arias²,

Molina³

et al. 2008

Developmental Psychobiology

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Rats exhibit taste avoidance and conditioned disgust reactions when stimulated with a tastant paired with lithium chloride (LiCl). Lithium-mediated activation of chemoreceptor nuclei at the brainstem appears to determine the acquisition of conditioned taste aversion (CTA) in adult rodents. Domperidone (DOM), an anti-emetic drug that does not cross the blood-brain barrier, was employed to analyze mechanisms underlying LiCl-mediated CTA in infant rats. On postnatal day 13 animals were given DOM followed by a pairing between intraoral saccharin and LiCl. Saccharin consumption at testing was lower in lithium-treated pups than in controls. DOM did not interfere with this LiCl-mediated taste avoidance but significantly decreased LiCl-mediated disgust reactions (head-shaking and wall climbing). Activation of the emetic system of the brainstem does not seem necessary for the acquisition of LiCl-mediated conditioned taste avoidance. Yet, these centers seem to be involved in the palatability shift resulting from taste-LiCl pairings. These results indicate an early dissociation between conditioned disgust reactions and conditioned taste avoidance.

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Evidence of lowest brain penetration of an antiemetic drug, metopimazine, compared to domperidone, metoclopramide and chlorpromazine, using an in vitro model of the blood–brain barrier

Cited by 46 publications

References 17 publications

Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control

Peripherally acting CB1-receptor antagonist: the relative importance of central and peripheral CB1 receptors in adiposity control

Gastroparesis, metoclopramide, and tardive dyskinesia: Risk revisited

Domperidone interferes with conditioned disgust reactions but not taste avoidance evoked by a LiCl‐paired taste in infant rats

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