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Pharmacokinetic profile of bitopertin, a selective GlyT1 inhibitor, in the rat

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Abstract

Bitopertin, a selective glycine transporter 1 (GlyT1) inhibitor, has been extensively studied for the treatment of schizophrenia, with known safety and tolerability profiles in the clinic. Whereas several rodent experiments have been reported, the pharmacokinetic (PK) profile of bitopertin in rodents has not been extensively reported, as only two studies disclosed limited PK parameters in male rats after oral administration. Here, we determined the PK profile of bitopertin in female Sprague-Dawley rats. Blood samples were taken serially, before and after sub-cutaneous (0.03, 0.1, 0.3, 1, and 3 mg/kg) or intra-venous (0.1 mg/kg) administration. Plasma levels were determined by high-performance liquid chromatography coupled with heat-assisted electrospray ionisation tandem mass spectrometry (HPLC-HESI MS/MS). Subsequently, PK parameters were calculated using non-compartmental analysis, including area under the curve (AUC), time (Tmax) to maximal plasma concentration (Cmax), clearance (CL), volume of distribution (Vz), as well as half-life (T1/2). Following sub-cutaneous injection, bitopertin exhibited dose-dependent AUC0-∞ (439.6–34,018.9 ng/mL) and Tmax (3.7–24.0 h), a very long terminal T1/2 (35.06–110.32 h) and low CL (0.07–0.13 L/h/kg), suggesting that bitopertin is slowly absorbed and eliminated in the rat. The observed relationship between dose and the extent of drug exposure (AUC) was linear. Following administration of all sub-cutaneous doses, measured bitopertin plasma levels were comparable to levels achieved with doses already administered in the clinic. We hope that our results will be useful in the design of pre-clinical experiments in which this drug will eventually be administered sub-cutaneously.

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Data are available upon written request to the corresponding author.

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Acknowledgements

IF holds a scholarship from Parkinson Canada. PH has had research support from Parkinson Canada, Parkinson Québec, Fonds de Recherche Québec – Santé, the Natural Sciences and Engineering Research Council of Canada, the Weston Brain Institute, the Michael J Fox Foundation for Parkinson’s Research, and Healthy Brains for Healthy Lives. FB is the holder of the Canada Research Chair in metrology of bioactive molecule and target discovery.

Author information

Authors and Affiliations

  1. Département de Pharmacologie et Physiologie, Université de Montréal, QC, Montreal, Canada

    Imane Frouni & Philippe Huot

  2. Neurodegenerative Disease Group, Montreal Neurological Institute-Hospital (The Neuro), Montreal, QC, Canada

    Imane Frouni, Dominique Bédard, Élodie Bourgeois-Cayer, Adjia Hamadjida & Philippe Huot

  3. Plateforme de Pharmacocinétique, Centre de Recherche du Centre Hospitalier de l’, Université de Montréal, QC, Montreal, Canada

    Fleur Gaudette

  4. Département de Biomédecine Vétérinaire, Faculté de Médecine Vétérinaire, Université de Montréal, Saint-Hyacinthe, QC, Canada

    Francis Beaudry

  5. Centre de Recherche sur le Cerveau et l’Apprentissage (CIRCA), Université de Montréal, Québec, Montréal, Canada

    Francis Beaudry

  6. Movement Disorder Clinic, Division of Neurology, Department of Neurosciences, McGill University Health Centre, Montreal, QC, Canada

    Philippe Huot

  7. Department of Neurology and Neurosurgery, McGill University, Montreal, QC, Canada

    Philippe Huot

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  1. Imane Frouni
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  2. Dominique Bédard
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  4. Adjia Hamadjida
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  5. Fleur Gaudette
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  6. Francis Beaudry
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  7. Philippe Huot
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Contributions

1) Research project: A. Conception, B. Organisation, C. Execution.

2) Manuscript: A. Writing of the first draft, B. Review and critique.

IF: 1B, 1C, 2A, 2B; DB: 1B, 1C, 2B; EBC: 1C, 2B; AH: 1B; 2B; FG: 1A, 1B, 1C, 2B; FB: 1A, 1B, 1C, 2B; PH: 1A, 1B, 2B.

Corresponding author

Correspondence to Philippe Huot.

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Ethics approval

This study was approved by the ethics committee of McGill University and the Montreal Neurological Institute-Hospital (The Neuro, Animal Use Protocol 2017–7922) in accordance with the regulations defined by the Canadian Council on Animal Care.

Competing interests

There are no conflicts of interest. PH has received payments from Neurodiem, AbbVie, Sanford Burnham Prebys, Sunovion, adMare BioInnovations, ConSynance Therapeutics, and Throughline Strategy.

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Frouni, I., Bédard, D., Bourgeois-Cayer, É. et al. Pharmacokinetic profile of bitopertin, a selective GlyT1 inhibitor, in the rat. Naunyn-Schmiedeberg's Arch Pharmacol 396, 1053–1060 (2023). https://doi.org/10.1007/s00210-022-02378-1

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