Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Special Sections
    • 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
  • Submit
  • 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
    • Special Sections
    • 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
  • Submit
  • Visit jpet on Facebook
  • Follow jpet on Twitter
  • Follow jpet on LinkedIn
Research ArticleNEUROPHARMACOLOGY

Uptake of Imipramine in Rat Liver Lysosomes In Vitro and Its Inhibition by Basic Drugs

Junko Ishizaki, Koichi Yokogawa, Fujio Ichimura and Shoji Ohkuma
Journal of Pharmacology and Experimental Therapeutics September 2000, 294 (3) 1088-1098;
Junko Ishizaki
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Koichi Yokogawa
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Fujio Ichimura
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Shoji Ohkuma
  • 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
Loading

Abstract

We investigated the uptake of imipramine (IMP) in highly purified lysosomes from rat liver and its inhibition by a variety of basic drugs in vitro. The uptake of [3H]IMP into lysosomes peaked in less than 20 s, showing little temperature dependency or countertransport phenomena. It was accelerated by increase of extralysosomal pH, stimulated by Mg2+-ATP in KCl buffer, and suppressed by acidic ionophores. However, the uptake of [3H]IMP in lysosomes was approximately 140-fold higher than the value expected from the pH-partition theory. IMP and other weak lipophilic bases like chlorpromazine and propranolol raised the intralysosomal pH, and their potency was stronger than that of NH4Cl, a typical pH-perturbing weak base. A variety of basic drugs inhibited the uptakes of [3H]IMP and [14C]methylamine into lysosomes, their 50% inhibitory concentrations (IC50) being almost the same for [3H]IMP and [14C]methylamine uptake (r = 0.842). A high correlation (r = 0.946) was observed between the IC50 values (for the inhibition of [3H]IMP uptake) and the lipophilicity (Poct values). These results suggest that the accumulation of lipophilic basic drugs is driven primarily by the transmembrane pH difference (pH-partition theory) but with the involvement of some additional mechanism(s) related to drug lipophilicity, possibly binding (partition or adsorption) to lipophilic substance(s) and/or aggregation within lysosomes. Based on this idea, we have established a model that described and successfully simulated the weak base-induced pH increase, the accumulation of a lipophilic weak base (IMP), and the inhibition of accumulation of IMP by lipophilic basic drugs.

Footnotes

  • Send reprint requests to: Shoji Ohkuma, Department of Molecular and Cellular Biology, Faculty of Pharmaceutical Sciences, Kanazawa University, Takara-machi 13-1, Kanazawa, Ishikawa 920-0934, Japan. E-mail: ohkuma{at}kenroku.kanazawa-u.ac.jp

  • ↵FN1 This study was supported in part by grants from the Ministry of Education, Science, Sports and Culture of Japan. This work was performed partly to fulfill a Ph.D. dissertation (J.I.) submitted to the Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan (1999) and was presented at the Annual Meeting of the Japanese Society for the Study of Xenobiotics, Hamamatsu, Japan (October, 1999).

  • Received for publication January 14, 2000.

  • Abbreviations:
    IMP
    imipramine
    AMA
    amantadine
    ATR
    atropine
    BAF
    bafilomycin A1
    CPZ
    chlorpromazine
    CQ
    chloroquine
    ΔpH
    transmembrane pH gradient
    DTZ
    diltiazem
    FD
    fluorescein isothiocyanate-dextran
    MeNH2
    methylamine
    NIG
    nigericin
    Poct
    octanol-water partition coefficient of the nonionized drug
    QN
    quinine
    PPR
    propranolol
    TFP
    trifluoperazine
    TMAH
    tetramethylammonium hydroxide
    V-ATPase
    vacuolar-type H+-ATPase
    VP
    verapamil
    • Accepted May 22, 2000.
  • 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: 294 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 294, Issue 3
1 Sep 2000
  • Table of Contents
  • About the Cover
  • Index by author
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.
Uptake of Imipramine in Rat Liver Lysosomes In Vitro and Its Inhibition by Basic Drugs
(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

Uptake of Imipramine in Rat Liver Lysosomes In Vitro and Its Inhibition by Basic Drugs

Junko Ishizaki, Koichi Yokogawa, Fujio Ichimura and Shoji Ohkuma
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1088-1098;

Citation Manager Formats

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

Share
Research ArticleNEUROPHARMACOLOGY

Uptake of Imipramine in Rat Liver Lysosomes In Vitro and Its Inhibition by Basic Drugs

Junko Ishizaki, Koichi Yokogawa, Fujio Ichimura and Shoji Ohkuma
Journal of Pharmacology and Experimental Therapeutics September 1, 2000, 294 (3) 1088-1098;
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Experimental Procedures
    • Results
    • Discussion
    • Acknowledgments
    • Base Accumulation and Intralysosomal pH Based on Simple pH-Partition Theory.
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • D1 agonist vs. methylphenidate on PFC working memory
  • Iclepertin (BI 425809) in schizophrenia-related models
  • Obesity Thwarts Preconditioning in TBI
Show more Neuropharmacology

Similar Articles

Advertisement
  • 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 © 2022 by the American Society for Pharmacology and Experimental Therapeutics