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
OtherDRUG METABOLISM AND DISPOSITION

Temocaprilat, a Novel Angiotensin-Converting Enzyme Inhibitor, is Excreted in Bile via an ATP-dependent Active Transporter (cMOAT) That is Deficient in Eisai Hyperbilirubinemic Mutant Rats (EHBR)

Hitoshi Ishizuka, Kumiko Konno, Hideo Naganuma, Kunihiro Sasahara, Yukinori Kawahara, Kayoko Niinuma, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics March 1997, 280 (3) 1304-1311;
Hitoshi Ishizuka
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kumiko Konno
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hideo Naganuma
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kunihiro Sasahara
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yukinori Kawahara
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kayoko Niinuma
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hiroshi Suzuki
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Yuichi Sugiyama
  • 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

Temocapril · HCl (α-{(2S,6R)-6-[(1S)-1-ethoxy-carbonyl-3-phenyl-propyl]amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4yl}acetic acid hydrochloride) is a novel prodrug of an angiotensin-converting enzyme (ACE) inhibitor. Unlike many other ACE inhibitors, its pharmacologically active metabolite,temocaprilat, is excreted predominantly in bile. To investigate the mechanism for the biliary excretion of temocaprilat, we performed in vivo and in vitro experiments using mutant Eisai hyperbilirubinemic rats EHBR) whose canalicular multispecific organic anion transporter (cMOAT) is hereditarily defective. Biliary clearance of temocaprilat after i.v. administration of [14C]temocapril · HCl (1.0 mg/kg) in EHBR was significantly lower than that in Sprague-Dawley rats (5.00 ml/min/kg for Sprague-Dawley rats vs. 0.25 ml/min/kg for EHBR). The uptake of temocaprilat into canalicular membrane vesicles (CMVs) prepared from Sprague-Dawley rats was stimulated in the presence of ATP, whereas little stimulation was observed in CMVs from EHBR. The initial uptake rate of ATP-dependent transport of temocaprilat showed saturation kinetics; we obtained an apparentV max value of 1.14 nmol/min/mg protein and aKm value 92.5 μM. ATP-dependent transport of temocaprilat was competitively inhibited by 2,4-dinitrophenyl-S-glutathione, a typical substrate for cMOAT with an inhibition constant (Ki ) of 25.8 μM. The Km value for the uptake of 2,4-dinitrophenyl-S-glutathione into CMVs (Km = 29.6 μM) was consistent with thisKi value. In addition, the ATP-dependent uptake of 2,4-dinitrophenyl-S-glutathione was inhibited by temocaprilat in a concentration-dependent manner. Active forms of some ACE inhibitors (benazepril, cilazapril, delapril, enalapril and imidapril) did not affect the transport of temocaprilat into CMVs even at concentrations as high as 200 μM. These data suggest that temocaprilat is effectively excreted in bile via cMOAT that is deficient in EHBR and that many of other ACE inhibitors have low affinity for cMOAT.

Footnotes

  • Send reprint requests to: Hitoshi Ishizuka, Analytical and Metabolic Research Laboratories, Sankyo Co., Ltd., 2-58, Hiromachi 1-chome, Shinagawa-ku, Tokyo 140, Japan.

  • Abbreviations:
    cMOAT
    canalicular multispecific organic anion transporter
    CMVs
    canalicular membrane vesicles
    SDR
    Sprague-Dawley rats
    EHBR
    Eisai hyperbilirubinemic rats
    DNP-SG
    2,4-dinitrophenyl-S-glutathione
    ACE
    angiotensin-converting enzyme
    ALP
    alkaline phosphatase
    LAP
    leucine aminopeptidase
    γ-GTPase
    γ-glutamyl transpeptidase
    Cmax
    maximum concentration
    AUC
    area under the curve
    Tmax
    time to maximum concentration
    CLbile
    biliary clearance
    DBSP
    dibromosulfophthalein
    ICG
    indocyanine green
    LG
    liquiritigenin
    E3040
    6-hydroxy-5, 7-dimethyl-2-methylamino-4-(3-pyridylmethyl) benzothiazole
    hMRP
    human multidrug resistance-associated protein
    ABC
    ATP-binding cassette
    PCR
    polymerase chain reaction
    • Received July 9, 1996.
    • Accepted November 8, 1996.
  • 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
Vol. 280, Issue 3
1 Mar 1997
  • Table of Contents
  • 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.
Temocaprilat, a Novel Angiotensin-Converting Enzyme Inhibitor, is Excreted in Bile via an ATP-dependent Active Transporter (cMOAT) That is Deficient in Eisai Hyperbilirubinemic Mutant Rats (EHBR)
(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
OtherDRUG METABOLISM AND DISPOSITION

Temocaprilat, a Novel Angiotensin-Converting Enzyme Inhibitor, is Excreted in Bile via an ATP-dependent Active Transporter (cMOAT) That is Deficient in Eisai Hyperbilirubinemic Mutant Rats (EHBR)

Hitoshi Ishizuka, Kumiko Konno, Hideo Naganuma, Kunihiro Sasahara, Yukinori Kawahara, Kayoko Niinuma, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1304-1311;

Citation Manager Formats

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

Share
OtherDRUG METABOLISM AND DISPOSITION

Temocaprilat, a Novel Angiotensin-Converting Enzyme Inhibitor, is Excreted in Bile via an ATP-dependent Active Transporter (cMOAT) That is Deficient in Eisai Hyperbilirubinemic Mutant Rats (EHBR)

Hitoshi Ishizuka, Kumiko Konno, Hideo Naganuma, Kunihiro Sasahara, Yukinori Kawahara, Kayoko Niinuma, Hiroshi Suzuki and Yuichi Sugiyama
Journal of Pharmacology and Experimental Therapeutics March 1, 1997, 280 (3) 1304-1311;
Reddit logo Twitter logo Facebook logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Materials and Methods
    • Results
    • Discussion
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • A New Interpretation of Salicylic Acid Transport across the Lipid Bilayer: Implications of pH-Dependent but not Carrier-Mediated Absorption from the Gastrointestinal Tract
  • Characterization of Efflux Transport of Organic Anions in a Mouse Brain Capillary Endothelial Cell Line
  • Activation of Human Liver 3α-Hydroxysteroid Dehydrogenase by Clofibrate Derivatives
Show more DRUG METABOLISM AND DISPOSITION

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 © 2023 by the American Society for Pharmacology and Experimental Therapeutics