Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Journal of Pharmacology and Experimental Therapeutics
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Journal of Pharmacology and Experimental Therapeutics

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleNeuropharmacology

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 November 2020, 375 (2) 376-384; DOI: https://doi.org/10.1124/jpet.120.000164
Shuhei Ishikawa
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Masaki Kobayashi
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Naoki Hashimoto
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hideaki Mikami
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Akihiko Tanimura
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Katsuya Narumi
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ayako Furugen
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ichiro Kusumi
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Ken Iseki
Laboratory of Clinical Pharmaceutics and Therapeutics, Division of Pharmasciences, Faculty of Pharmaceutical Sciences (S.I., M.K., H.M., K.N., A.F., K.I.) and Education Research Center for Clinical Pharmacy, Faculty of Pharmaceutical Sciences (M.K.), Hokkaido University, Sapporo, Japan; Department of Pharmacy, Hokkaido University Hospital, Sapporo, Japan (S.I.); Department of Psychiatry, Hokkaido University Graduate School of Medicine, Sapporo, Japan (N.H., I.K.); and Department of Pharmacology, School of Dentistry, Health Sciences University of Hokkaido, Sapporo, Japan (A.T.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF
Loading

Abstract

Clozapine-induced sialorrhea (CIS) is a common side effect of clozapine. There is no established standard treatment of 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 the 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, but 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.

Footnotes

    • Received June 11, 2020.
    • Accepted August 12, 2020.
  • ↵1 Current affiliation: Department of Psychiatry, Hokkaido University Hospital, Sapporo, Japan.

  • This study was supported by the Japan Society for the Promotion of Science (JSPS) [KAKENHI Grant Numbers 15H00540, 16H00509, and 19H0035409] and Takeda Science Foundation.

  • Conflict of interests: S.I., M.K., H.M., A.T., K.N., A.F., and K.I. declare that they have no conflicts of interest with the contents of this article. N.H. received personal fees from Janssen Pharmaceutical, Yoshitomiyakuhin, Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Novartis Pharma, and Meiji Seika Pharma. I.K. has received honoraria from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Lundbeck, Meiji Seika Pharma, MSD, Mylan, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Shire, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Tsumura, and Yoshitomiyakuhin, and has received research/grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Kyowa Hakko Kirin, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, and Takeda Pharmaceutical, and is a member of the advisory board of Dainippon Sumitomo Pharma.

  • https://doi.org/10.1124/jpet.120.000164.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics
View Full Text

JPET articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Journal of Pharmacology and Experimental Therapeutics: 375 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 375, Issue 2
1 Nov 2020
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover
  • Index by author
  • Editorial Board (PDF)
  • Front Matter (PDF)
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Journal of Pharmacology and Experimental Therapeutics article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Association Between N-Desmethylclozapine and Clozapine-Induced Sialorrhea: Involvement of Increased Nocturnal Salivary Secretion via Muscarinic Receptors by N-Desmethylclozapine
(Your Name) has forwarded a page to you from Journal of Pharmacology and Experimental Therapeutics
(Your Name) thought you would be interested in this article in Journal of Pharmacology and Experimental Therapeutics.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleNeuropharmacology

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 November 1, 2020, 375 (2) 376-384; DOI: https://doi.org/10.1124/jpet.120.000164

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleNeuropharmacology

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 November 1, 2020, 375 (2) 376-384; DOI: https://doi.org/10.1124/jpet.120.000164
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Introduction
    • Materials and Methods
    • Results
    • Discussion
    • Acknowledgments
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF + SI
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • Oxysterols and ethanol
  • P-glycoprotein Apical Efflux Ratio for Compound Optimization
  • Pharmacology of Carbamate Insecticides at MT1 & MT2
Show more Neuropharmacology

Similar Articles

  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About JPET
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Molecular Pharmacology
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0103 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics