Tacrolimus pharmacokinetics and gut microbiota : from mechanistic to clinical investigations

To prevent graft rejection, transplant patients undergo a lifelong immunosuppressive treatment, of which tacrolimus (TAC) is a key drug. Despite its efficacy, the narrow therapeutic index of TAC and the high inter- and intra-patient pharmacokinetic (PK) variabilities make its clinical use complex and increase the risk of therapeutic failure. In this thesis, we explored a new element that could contribute to these PK variabilities: the intestinal microbiota. Using in vivo and in vitro preclinical approaches, we demonstrated that gut bacteria affect the intestinal absorption of TAC through the modulation of the expression of the ABCB1 efflux pump (aka, P-glycoprotein). In parallel, a cross-sectional clinical study has been conducted in stabilised kidney transplant patients. We observed that the presence of specific intestinal bacteria associates with the PK parameters of TAC. Our work confirms the role of the gut microbiota as a contributor to TAC PK variability and opens up new avenues of research to improve clinical practice in fine.(BIFA - Sciences biomédicales et pharmaceutiques) -- UCL, 202