The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function.

Movin-Osswald, Gunilla; Boelaert, Johan R.; Hammarlund‐Udenaes, Margareta; Lb, Nilsson

doi:10.1111/j.1365-2125.1993.tb04191.x

Cited by 11 publications

(3 citation statements)

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“…A decrease in urinary pH increases both the percentage of the drug excreted unchanged in the urine and the elimination rate. Plasma half-life of remoxipride is prolonged and elimination slowed in patients with renal or liver disorders, as well as in elderly patients (80,122). The disposition of remoxipride is similar in Chinese schizophrenic patients (66) and also in elderly psychiatric patients with or without tardive dyskinesia (128).…”

Section: Human Pharmacokineticsmentioning

confidence: 99%

Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D₂ Receptor Antagonist

Nadal

2001

CNS Drug Reviews

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Remoxipride is a substituted benzamide that acts as a weak but very selective antagonist of dopamine D 2 receptors. It was introduced by Astra (Roxiam ® ) at the end of the eighties and was prescribed as an atypical antipsychotic. This article reviews its putative selective effects on mesolimbic versus nigrostriatal dopaminergic systems. In animals, remoxipride has minimal cataleptic effects at doses that block dopamine agonist-induced hyperactivity. These findings are predictive of antipsychotic activity with a low likelihood of extrapyramidal symptoms. Remoxipride also appears to be effective in more recent animal models of schizophrenia, such as latent inhibition or prepulse inhibition. In clinical studies, remoxipride shows a relatively low incidence of extrapyramidal side effects and its effects on prolactin release are short-lasting and generally mild. The clinical efficacy of remoxipride is similar to that of haloperidol or chlorpromazine. Although its clinical use was severely restricted in 1993, due to reports of aplastic anemia in some patients receiving remoxipride, this drug has been found to exhibit relatively high selectivity for dopamine D 2 receptors making remoxipride an interesting tool for neurochemical and behavioral studies.

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Section: Human Pharmacokineticsmentioning

confidence: 99%

Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D₂ Receptor Antagonist

Nadal

2001

CNS Drug Reviews

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“…However, in humans, remoxipride is metabolized mainly via oxidation (25), which may not be saturated at these concentrations. Indeed, linear elimination was identified for remoxipride in humans (26).…”

Section: Pharmacokineticsmentioning

confidence: 99%

Revealing the Neuroendocrine Response After Remoxipride Treatment Using Multi-Biomarker Discovery and Quantifying It by PK/PD Modeling

Brink

Wong

Gülave

et al. 2016

AAPS J

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Abstract.To reveal unknown and potentially important mechanisms of drug action, multibiomarker discovery approaches are increasingly used. Time-course relationships between drug action and multi-biomarker profiles, however, are typically missing, while such relationships will provide increased insight in the underlying body processes. The aim of this study was to investigate the effect of the dopamine D2 antagonist remoxipride on the neuroendocrine system. Different doses of remoxipride (0, 0.7, 5.2, or 14 mg/kg) were administered to rats by intravenous infusion. Serial brain extracellular fluid (brainECF) and plasma samples were collected and analyzed for remoxipride pharmacokinetics (PK). Plasma samples were analyzed for concentrations of the eight pituitary-related hormones as a function of time. A Mann-Whitney test was used to identify the responding hormones, which were further analyzed by pharmacokinetic/ pharmacodynamic (PK/PD) modeling. A three-compartment PK model adequately described remoxipride PK in plasma and brainECF. Not only plasma PRL, but also adrenocorticotrophic hormone (ACTH) concentrations were increased, the latter especially at higher concentrations of remoxipride. Brain-derived neurotropic factor (BDNF), follicle stimulating hormone (FSH), growth hormone (GH), luteinizing hormone (LH), and thyroid stimulating hormones (TSH) did not respond to remoxipride at the tested doses, while oxytocin (OXT) measurements were below limit of quantification. Precursor pool models were linked to brainECF remoxipride PK by E max drug effect models, which could accurately describe the PRL and ACTH responses. To conclude, this study shows how a multi-biomarker identification approach combined with PK/PD modeling can reveal and quantify a neuroendocrine multi-biomarker response for single drug action.

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“…Remoxripride is known to be metabolized by CYP2D6 in humans (Marsh et al, 1999; Movin-Osswald et al, 1993). While concrete evidence is lacking to definitively identify the responsible rat CYP2D isoform for remoxipride metabolism (Miksys et al, 2000; Tyndale et al, 1999), it is certain that the CYP2D isoforms in rats fulfil the role of CYP2D6 in humans (Grobe et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Exploring Kp,uu,BBB Values Smaller than Unity in Remoxipride: A Physiologically-Based CNS Model Approach Highlighting Brain Metabolism in Drugs with Passive Blood-Brain Barrier Transport

Zhang,

Vuist,

Rottschäfer

et al. 2024

Preprint

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Abstract(Aim)Kp,uu,BBBvalues are crucial indicators of drug distribution into the brain, representing the steady-state relationship between unbound concentrations in plasma and in brain extracellular fluid (brainECF). Kp,uu,BBBvalues < 1 are often interpreted as indicators of dominant active efflux transport processes at the blood-brain barrier (BBB). However, the potential impact of brain metabolism on this value is typically not addressed. In this study, we investigated the brain distribution of remoxipride, as a paradigm compound for passive BBB transport with yet unexplained brain elimination that was hypothesized to represent brain metabolism.(Methods)The physiologically-based LeiCNS pharmacokinetic predictor (LeiCNS-PK model) was used to compare brain distribution of remoxipride with and without Michaelis-Menten kinetics at the BBB and/or brain cell organelle levels. To that end, multiple in-house (IV 0.7, 3.5, 4, 5.2, 7, 8, 14 and 16 mg/kg) and external (IV 4 and 8 mg/kg) rat microdialysis studies plasma and brainECF data were analysed.(Results)The incorporation of active elimination through presumed brain metabolism of remoxipride in the LeiCNS-PK model significantly improved the prediction accuracy of experimentally observed brainECF profiles of this drug. The model integrated with brain metabolism in both barriers and organelles levels is named LeiCNS-PK3.5.(Conclusion)For drugs with Kp,uu,BBBvalues < 1, not only the current interpretation of dominant BBB efflux transport, but also potential brain metabolism needs to be considered, especially because these may be concentration dependent. This will improve the mechanistic understanding of the processes that determine brain PK profiles.

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The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function.

Cited by 11 publications

References 11 publications

Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D₂ Receptor Antagonist

Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D₂ Receptor Antagonist

Revealing the Neuroendocrine Response After Remoxipride Treatment Using Multi-Biomarker Discovery and Quantifying It by PK/PD Modeling

Exploring Kp,uu,BBB Values Smaller than Unity in Remoxipride: A Physiologically-Based CNS Model Approach Highlighting Brain Metabolism in Drugs with Passive Blood-Brain Barrier Transport

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The pharmacokinetics of remoxipride and metabolites in patients with various degrees of renal function.

Cited by 11 publications

References 11 publications

Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D2 Receptor Antagonist

Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D2 Receptor Antagonist

Revealing the Neuroendocrine Response After Remoxipride Treatment Using Multi-Biomarker Discovery and Quantifying It by PK/PD Modeling

Exploring Kp,uu,BBB Values Smaller than Unity in Remoxipride: A Physiologically-Based CNS Model Approach Highlighting Brain Metabolism in Drugs with Passive Blood-Brain Barrier Transport

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Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D₂ Receptor Antagonist

Pharmacology of the Atypical Antipsychotic Remoxipride, a Dopamine D₂ Receptor Antagonist