Dose, Kidney Function, and a Drug-Excipient Interaction Impair Mycophenolate Mofetil Prodrug Activation in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVE: Current immunosuppressive treatment to prevent graft rejection in organ transplant recipients commonly includes mycophenolate mofetil (MMF) and a calcineurin inhibitor. After absorption, MMF is activated to mycophenolate (MPA) by the carboxylesterase (CES) enzymes, which is considered to occur rapidly and completely. Recent research utilizing pharmacometabolomics (PMx), however, identified an unknown/unreported MMF glucuronide metabolite in several kidney transplant recipients (KTR). This finding indicates incomplete MMF prodrug activation by CES, thereby suggesting enzyme saturation and/or inhibition, which warrants further study. In this work, we aimed to identify clinical factors that could (partially) explain incomplete MMF activation as observed in KTR. METHODS: We analyzed untargeted urinary PMx data to determine MMF prodrug activation in 321 KTR from the TransplantLines Biobank and Cohort Study (NCT03272841) and 403 KTR from the TransplantLines Food and Nutrition Biobank and Cohort Study (NCT02811835). Beta regression was used to associate incomplete MMF activation with clinical parameters. Subsequently, in vitro experiments using human S9 liver extracts were performed to compare the influence of potential CES inhibitors on MMF activation. RESULTS: Beta regression linked an impaired MMF activation with increasing MMF dose and kidney function as well as with cyclosporine (CsA) use. Regarding the latter, in vitro experiments revealed a decreased MMF activation caused by the pharmaceutical excipient Kolliphor(®) EL, which is present in CsA capsules, rather than by CsA itself. CONCLUSION: Substantially reduced MMF prodrug activation was observed in large numbers of KTR, indicating relevant attenuation of the MMF-converting CES enzymes, which may be due to enzyme saturation and inhibition. However, there may be other factors affecting MMF activation, which require elucidation to improve immunosuppression therapy.