RT Journal Article
SR Electronic
T1 Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 426197
DO 10.1101/426197
A1 Guo, Yukuang
A1 Crnkovic, Camila Manoel
A1 Won, Kyoung-Jae
A1 Yang, Xiaotong
A1 Lee, John Richard
A1 Orjala, Jimmy
A1 Lee, Hyunwoo
A1 Jeong, Hyunyoung
YR 2018
UL http://biorxiv.org/content/early/2018/10/01/426197.abstract
AB 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.AbbreviationsBEIBiodefense and Emerging InfectionsBrdU5-Bromo-2′-deoxyuridineCOSYHomonuclear 1H-1H Correlation SpectroscopyDEPTQDistorsionless enhancement by polarization transfer quaternary HMBC Heteronuclear multiple bond correlation spectroscopyHPLCHigh performance liquid chromatographyHRMSHigh resolution mass spectrometryHSQCHeteronuclear single quantum coherence spectroscopyIRInfrared spectroscopyMS/MSTandem mass spectrometryNMRNuclear magnetic resonance spectroscopyPBMCPeripheral blood mononuclear cellsP-gpP-glycoproteinPHAPhytohemagglutininTMB3,3′,5,5′-TetramethylbenzidineTOCSYTotal correlated spectroscopy