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OtherNeuropharmacology

Association between N-desmethylclozapine and clozapine-induced sialorrhea: Involvement of increased nocturnal salivary secretion via muscarinic receptors by N-desmethylclozapine

Shuhei Ishikawa, Masaki Kobayashi, Naoki Hashimoto, Hideaki Mikami, Akihiko Tanimura, Katsuya Narumi, Ayako Furugen, Ichiro Kusumi and Ken Iseki
Journal of Pharmacology and Experimental Therapeutics August 29, 2020, JPET-AR-2020-000164; DOI: https://doi.org/10.1124/jpet.120.000164
Shuhei Ishikawa
1Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
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Masaki Kobayashi
1Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
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  • For correspondence: masaki@pharm.hokudai.ac.jp
Naoki Hashimoto
2Psychiatry, Hokkaido University Graduate School of Medicine, Japan
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Hideaki Mikami
1Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
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Akihiko Tanimura
3Pharmacology, Health Sciences University of Hokkaido, Japan
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Katsuya Narumi
1Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
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Ayako Furugen
1Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
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Ichiro Kusumi
2Psychiatry, Hokkaido University Graduate School of Medicine, Japan
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Ken Iseki
1Faculty of Pharmaceutical Sciences, Hokkaido University, Japan
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Abstract

Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment for CIS since the underlying mechanism remains unknown. This study aimed to elucidate the mechanisms involved in CIS. In our clinical study, a prospective observational study evaluated the association between serum and saliva concentrations of clozapine or its metabolites and drooling severity and frequency scale (DSFS) score. In our in vivo study, we first developed a new CIS animal model; subsequently, we measured salivary secretion and concentrations of clozapine or its metabolites in the animal model. In our in vitro study, we measured the calcium ion (Ca2+) response to evaluate the effect of clozapine or its metabolites on human salivary gland cell line (HSY cells), and then examined whether their effect was inhibited by atropine. In our clinical study, serum and saliva N-desmethylclozapine concentrations were significantly correlated with nocturnal DSFS score. In our in vivo study, daily single oral administration of 100 mg/kg clozapine for 7 days significantly increased salivary secretion in rats. Furthermore, N-desmethylclozapine concentrations in serum and submandibular glands of rats were higher than clozapine concentrations. In our in vitro study, N-desmethylclozapine only elicited an increase in the intracellular Ca2+ in HSY cells. N-desmethylclozapine-induced Ca2+ responses were inhibited by atropine. These results suggest that N-desmethylclozapine is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors. Moreover, our developed animal model that reflects CIS in clinical condition plays a key role as a bridge between basic and clinical research.

Significance Statement Clozapine-induced sialorrhea (CIS) is a severe and frequent adverse reaction. Although the mechanism underlying CIS is less well understood. This paper reports that N-desmethylclozapine, a metabolite of clozapine, is implicated in CIS by increasing nocturnal salivation via the muscarinic receptors, and that oral administration of clozapine at 100 mg/kg once daily for 7 days to rat is the optimum method for establishing the new animal model reflecting the clinical scenario of CIS.

  • adverse drug reactions
  • animal models
  • animal/nonclinical/preclinical
  • antipsychotics
  • clinical pharmacology
  • human/clinical
  • Muscarinic cholinergic receptors
  • schizophrenia
  • Copyright © 2020 American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 376 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 376, Issue 2
1 Feb 2021
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OtherNeuropharmacology

Association between N-desmethylclozapine and CIS

Shuhei Ishikawa, Masaki Kobayashi, Naoki Hashimoto, Hideaki Mikami, Akihiko Tanimura, Katsuya Narumi, Ayako Furugen, Ichiro Kusumi and Ken Iseki
Journal of Pharmacology and Experimental Therapeutics August 29, 2020, JPET-AR-2020-000164; DOI: https://doi.org/10.1124/jpet.120.000164

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OtherNeuropharmacology

Association between N-desmethylclozapine and CIS

Shuhei Ishikawa, Masaki Kobayashi, Naoki Hashimoto, Hideaki Mikami, Akihiko Tanimura, Katsuya Narumi, Ayako Furugen, Ichiro Kusumi and Ken Iseki
Journal of Pharmacology and Experimental Therapeutics August 29, 2020, JPET-AR-2020-000164; DOI: https://doi.org/10.1124/jpet.120.000164
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