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 ArticleMetabolism, Transport, and Pharmacogenomics

A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure

Stephen Fowler, Heidemarie Kletzl, Moshe Finel, Nenad Manevski, Paul Schmid, Dietrich Tuerck, Roger D. Norcross, Marius C. Hoener, Olivia Spleiss and Victor A. Iglesias
Journal of Pharmacology and Experimental Therapeutics February 2015, 352 (2) 358-367; DOI: https://doi.org/10.1124/jpet.114.220194
Stephen Fowler
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Heidemarie Kletzl
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Moshe Finel
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Nenad Manevski
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Paul Schmid
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Dietrich Tuerck
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Roger D. Norcross
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Marius C. Hoener
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Olivia Spleiss
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Victor A. Iglesias
Roche Pharma Research and Early Development, Roche Innovation Center Basel, Basel, Switzerland (S.F., H.K., P.S., D.T., R.D.N., M.C.H., O.S., V.A.I.); and Pharmaceutical Chemistry, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland (M.F., N.M.)
  • 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

RO5263397 [(S)-4-(3-fluoro-2-methyl-phenyl)-4,5-dihydro-oxazol-2-ylamine], a new compound that showed promising results in animal models of schizophrenia, is mainly metabolized in humans by N-glucuronidation. Enzyme studies, using the (then) available commercial uridine 5′-diphosphate-glucuronosyltransferases (UGTs), suggested that UGT1A4 is responsible for its conjugation. In the first clinical trial, in which RO5263397 was administered orally to healthy human volunteers, a 136-fold above-average systemic exposure to the parent compound was found in one of the participants. Further administration in this trial identified two more such poor metabolizers, all three of African origin. Additional in vitro studies with recombinant UGTs showed that the contribution of UGT2B10 to RO5263397 glucuronidation is much higher than UGT1A4 at clinically relevant concentrations. DNA sequencing in all of these poor metabolizers identified a previously uncharacterized splice site mutation that prevents assembly of full-length UGT2B10 mRNA and thus functional UGT2B10 protein expression. Further DNA database analyses revealed the UGT2B10 splice site mutation to be highly frequent in individuals of African origin (45%), moderately frequent in Asians (8%) and almost unrepresented in Caucasians (<1%). A prospective study using hepatocytes from 20 individual African donors demonstrated a >100-fold lower intrinsic clearance of RO5263397 in cells homozygous for the splice site variant allele. Our results highlight the need to include UGT2B10 when screening the human UGTs for the enzymes involved in the glucuronidation of a new compound, particularly when there is a possibility of N-glucuronidation. Moreover, this study demonstrates the importance of considering different ethnicities during drug development.

Footnotes

    • Received September 26, 2014.
    • Accepted December 10, 2014.
  • ↵1 Current affiliation: Novartis Pharmaceuticals Ltd., Basel, Switzerland.

  • S.F. and H.K. contributed equally to this work.

  • This research was supported by F. Hoffmann-La Roche Ltd.

  • M.F. is a coauthor on a patent application (no. 20100087493) claiming rights related to the use of UGT2B10 modulators to improve the pharmacokinetics of UGT2B10 substrates, but has no conflict of interest with respect to this work.

  • dx.doi.org/10.1124/jpet.114.220194.

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

  • Copyright © 2015 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: 352 (2)
Journal of Pharmacology and Experimental Therapeutics
Vol. 352, Issue 2
1 Feb 2015
  • 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.
A UGT2B10 Splicing Polymorphism Common in African Populations May Greatly Increase Drug Exposure
(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 ArticleMetabolism, Transport, and Pharmacogenomics

UGT2B10 Splice Variant Increases Drug Exposure in Africans

Stephen Fowler, Heidemarie Kletzl, Moshe Finel, Nenad Manevski, Paul Schmid, Dietrich Tuerck, Roger D. Norcross, Marius C. Hoener, Olivia Spleiss and Victor A. Iglesias
Journal of Pharmacology and Experimental Therapeutics February 1, 2015, 352 (2) 358-367; DOI: https://doi.org/10.1124/jpet.114.220194

Citation Manager Formats

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

Share
Research ArticleMetabolism, Transport, and Pharmacogenomics

UGT2B10 Splice Variant Increases Drug Exposure in Africans

Stephen Fowler, Heidemarie Kletzl, Moshe Finel, Nenad Manevski, Paul Schmid, Dietrich Tuerck, Roger D. Norcross, Marius C. Hoener, Olivia Spleiss and Victor A. Iglesias
Journal of Pharmacology and Experimental Therapeutics February 1, 2015, 352 (2) 358-367; DOI: https://doi.org/10.1124/jpet.114.220194
Reddit logo Twitter logo Facebook 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

  • HDL Mimetic 4F Modulates Aβ Distribution in Brain and Plasma
  • AOX1 Inhibition by Gefitinib, Erlotinib, and Metabolites
  • Catalytic Activity of CYP2C9 Variants
Show more Metabolism, Transport, and Pharmacogenomics

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