Commensal Gut Bacteria Convert the Immunosuppressant Tacrolimus to Less Potent Metabolites

• Published in: Drug metabolism and disposition Vol. 47; no. 3; pp. 194 - 202
• Main Authors: Guo, Yukuang, Crnkovic, Camila Manoel, Won, Kyoung-Jae, Yang, Xiaotong, Lee, John Richard, Orjala, Jimmy, Lee, Hyunwoo, Jeong, Hyunyoung
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.03.2019; American Society for Pharmacology and Experimental Therapeutics, Inc; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Administration, Oral; Adult; Adults; Aged; Bacteria; Cells, Cultured; Dosage; Dose-Response Relationship, Drug; Faecalibacterium prausnitzii - metabolism; Feces - chemistry; Female; Gastrointestinal Microbiome - physiology; Graft Rejection - immunology; Graft Rejection - prevention & control; Healthy Volunteers; Humans; Immunosuppression Therapy - methods; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - analysis; Immunosuppressive Agents - metabolism; Kidney transplantation; Kidney Transplantation - adverse effects; Kidneys; Leukocytes (mononuclear); Leukocytes, Mononuclear - drug effects; Magnetic resonance spectroscopy; Male; Mass spectrometry; Mass spectroscopy; Metabolism; Metabolites; Microsomes; Middle Aged; NMR; Nuclear magnetic resonance; Peripheral blood mononuclear cells; Pharmacology; Purification; Symbiosis; Tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - analysis; Tacrolimus - metabolism; PBS; P-gp; rRNA; m/z; OD600; MS/MS; PBMC; HPLC
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.118.084772

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.