Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites

Yukuang Guo, Camila Manoel Crnkovic, Kyoung-Jae Won, Xiaotong Yang, John Richard Lee, Jimmy Orjala, Hyunwoo Lee, Hyunyoung Jeong
doi: https://doi.org/10.1101/426197
Yukuang Guo
1Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago
5Center for Biomolecular Sciences
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Camila Manoel Crnkovic
1Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kyoung-Jae Won
2Department of Pharmacy Practice, University of Illinois at Chicago
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Xiaotong Yang
4Department of Biopharmaceutical Sciences, University of Illinois at Chicago
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John Richard Lee
3Division of Nephrology and Hypertension, Department of Medicine, Weill Cornell Medicine
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jimmy Orjala
1Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago
5Center for Biomolecular Sciences
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hyunwoo Lee
1Department of Medicinal Chemistry and Pharmacognosy, University of Illinois at Chicago
5Center for Biomolecular Sciences
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Hyunyoung Jeong
2Department of Pharmacy Practice, University of Illinois at Chicago
4Department of Biopharmaceutical Sciences, University of Illinois at Chicago
5Center for Biomolecular Sciences
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

Tacrolimus exhibits low and variable drug exposure after oral dosing, but the contributing factors remain unclear. Based on our recent report showing a positive correlation between fecal abundance of Faecalibacterium prausnitzii and oral tacrolimus dose in kidney transplant patients, we tested whether F. prausnitzii and other gut abundant bacteria are capable of metabolizing tacrolimus. Incubation of F. prausnitzii with tacrolimus led to production of two compounds (the major one named M1), which was not observed upon tacrolimus incubation with hepatic microsomes. Isolation, purification, and structure elucidation using mass spectrometry and nuclear magnetic resonance spectroscopy indicated that M1 is a C-9 keto-reduction product of tacrolimus. Pharmacological activity testing using human peripheral blood mononuclear cells demonstrated that M1 is 15-fold less potent than tacrolimus as an immunosuppressant. Screening of 22 gut bacteria species revealed that most Clostridiales bacteria are extensive tacrolimus metabolizers. Tacrolimus conversion to M1 was verified in fresh stool samples from two healthy adults. M1 was also detected in the stool samples from kidney transplant recipients who had been taking tacrolimus orally. Together, this study presents gut bacteria metabolism as a previously unrecognized elimination route of tacrolimus, potentially contributing to the low and variable tacrolimus exposure after oral dosing.

Abbreviations
BEI
Biodefense and Emerging Infections
BrdU
5-Bromo-2′-deoxyuridine
COSY
Homonuclear 1H-1H Correlation Spectroscopy
DEPTQ
Distorsionless enhancement by polarization transfer quaternary HMBC Heteronuclear multiple bond correlation spectroscopy
HPLC
High performance liquid chromatography
HRMS
High resolution mass spectrometry
HSQC
Heteronuclear single quantum coherence spectroscopy
IR
Infrared spectroscopy
MS/MS
Tandem mass spectrometry
NMR
Nuclear magnetic resonance spectroscopy
PBMC
Peripheral blood mononuclear cells
P-gp
P-glycoprotein
PHA
Phytohemagglutinin
TMB
3,3′,5,5′-Tetramethylbenzidine
TOCSY
Total correlated spectroscopy
Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
Back to top
PreviousNext
Posted October 01, 2018.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites
Yukuang Guo, Camila Manoel Crnkovic, Kyoung-Jae Won, Xiaotong Yang, John Richard Lee, Jimmy Orjala, Hyunwoo Lee, Hyunyoung Jeong
bioRxiv 426197; doi: https://doi.org/10.1101/426197
Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
Citation Tools
Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites
Yukuang Guo, Camila Manoel Crnkovic, Kyoung-Jae Won, Xiaotong Yang, John Richard Lee, Jimmy Orjala, Hyunwoo Lee, Hyunyoung Jeong
bioRxiv 426197; doi: https://doi.org/10.1101/426197

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Pharmacology and Toxicology
Subject Areas
All Articles
  • Animal Behavior and Cognition (2516)
  • Biochemistry (4961)
  • Bioengineering (3458)
  • Bioinformatics (15159)
  • Biophysics (6876)
  • Cancer Biology (5372)
  • Cell Biology (7699)
  • Clinical Trials (138)
  • Developmental Biology (4514)
  • Ecology (7120)
  • Epidemiology (2059)
  • Evolutionary Biology (10202)
  • Genetics (7494)
  • Genomics (9761)
  • Immunology (4811)
  • Microbiology (13166)
  • Molecular Biology (5124)
  • Neuroscience (29332)
  • Paleontology (203)
  • Pathology (833)
  • Pharmacology and Toxicology (1459)
  • Physiology (2125)
  • Plant Biology (4728)
  • Scientific Communication and Education (1007)
  • Synthetic Biology (1336)
  • Systems Biology (4000)
  • Zoology (768)