Advertisement

Topics

Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites.

07:00 EST 31st December 2018 | BioPortfolio

Summary of "Commensal gut bacteria convert the immunosuppressant tacrolimus to less potent metabolites."

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.

Affiliation

Journal Details

This article was published in the following journal.

Name: Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Pages:

Links

DeepDyve research library

PubMed Articles [7476 Associated PubMed Articles listed on BioPortfolio]

Crossing the Mucosal Barrier: A Commensal Bacterium Gives Dengue Virus a Leg-Up in the Mosquito Midgut.

Commensal bacteria that colonize the midgut of Aedes aegypti mosquitoes can influence the transmission of arthropod-borne viruses. In this issue of Cell Host & Microbe, Wu et al. (2019) show that Ser...

Tacrolimus inhibits Th1 and Th17 responses in MuSK-antibody positive myasthenia gravis patients.

Muscle specific tyrosine kinase antibody positive myasthenia gravis (MuSK- MG) is characterized by autoantibodies against the MuSK protein of the neuromuscular junction resulting in weakness of bulbar...

Systemic Antibody Responses to Gut Commensal Bacteria: How and Why Do I Know You?

Population Pharmacokinetics of Tacrolimus in Transplant Recipients: What Did We Learn About Sources of Interindividual Variabilities?

Tacrolimus, a calcineurin inhibitor, is a common immunosuppressant prescribed after organ transplantation and has notable inter- and intrapatient pharmacokinetic variability. The sources of variabilit...

Very early introduction of everolimus in de novo liver transplantation: results of a multicenter, prospective, randomized trial (EPOCAL).

Early everolimus introduction and tacrolimus minimization after liver transplantation may represent a novel immunosuppressant approach. This phase 2, multicenter, randomized, open-label trial evaluate...

Clinical Trials [2469 Associated Clinical Trials listed on BioPortfolio]

Twice-daily Tacrolimus and Everolimus Convert to Once-daily Tacrolimus and Everolimus in Liver Transplant Recipient

It has been identified that nonadherence to immunosuppressant regimen may cause long-term graft failure and death in solid organ transplant recipients. Therefore, simplification of the imm...

Converting Elderly Kidney Transplant Recipients From Tacrolimus to Envarsus to Limit Neurological AE and Improve QOL

This study will investigate whether converting patients from FDA approved immediate-release tacrolimus to FDA approved extended release tacrolimus (Envarsus) reduces neurological side-effe...

Investigation of Potential Drug-drug Interactions Between Faldaprevir and the Immunosuppressant Drugs Cyclosporine or Tacrolimus

The primary objective of this trial is to investigate the effect of multiple-dose faldaprevir (FDV) on the single-dose pharmacokinetics of cyclosporine or tacrolimus

Protective Immunity Project 01

Patients who undergo kidney transplant must take medications to prevent organ rejection. There are standard immunosuppressant medications such as prednisone, tacrolimus (Prograf), mycophen...

Epidemiology of Fluoroquinolone Resistance in Human Commensal Flora in Patients Hospitalised in Medical Wards

Emergence of bacterial resistance to antibiotics, which is a major public health issue, appears to involve predominantly commensal flora. No data exists concerning risk factors for the car...

Medical and Biotech [MESH] Definitions

Members of a family of highly conserved proteins which are all cis-trans peptidyl-prolyl isomerases (PEPTIDYLPROLYL ISOMERASE). They bind the immunosuppressant drugs CYCLOSPORINE; TACROLIMUS and SIROLIMUS. They possess rotamase activity, which is inhibited by the immunosuppressant drugs that bind to them.

A 12-KDa tacrolimus binding protein that is found associated with and may modulate the function of calcium release channels. It is a peptidyl-prolyl cis/trans isomerase which is inhibited by both tacrolimus (commonly called FK506) and SIROLIMUS.

A family of immunophilin proteins that bind to the immunosuppressive drugs TACROLIMUS (also known as FK506) and SIROLIMUS. EC 5.2.1.-

A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.

A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that TACROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.

Advertisement
Quick Search
Advertisement
Advertisement

 


DeepDyve research library

Relevant Topics

Pharmacy
Pharmacy is the science and technique of preparing as well as dispensing drugs and medicines. It is a health profession that links health sciences with chemical sciences and aims to ensure the safe and effective use of pharmaceutical drugs. The scope of...

Hepatology
Hepatology is the study of liver, gallbladder, biliary tree, and pancreas, and diseases associated with them. This includes viral hepatitis, alcohol damage, cirrhosis and cancer. As modern lifestyles change, with alcoholism and cancer becoming more promi...


Searches Linking to this Article