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.
Footnotes
- Received October 1, 2018.
- Accepted December 27, 2018.
↵1 Y.G. and C.M.C. contributed equally to this work.
This work was supported by the National Institutes of Health [Grant K23 AI 124464] (to J.R.L.) and Chicago Biomedical Consortium [Catalyst Award C‐066] (to H.J.).
J.R.L. receives research support from BioFire Diagnostics, LLC. The other authors have no conflicts of interest.
An earlier version of this paper appears in bioRχiv under the doi 10.1101/426197.
↵This article has supplemental material available at dmd.aspetjournals.org.
- Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics