Extrahepatic metabolism of ibrutinib

• DOI: 10.1007/s10637-020-00970-x
• Publication Date: 2020-07-04T22:02:37Z
• Authors: Johannes J. M. Rood; Amer Jamalpoor; Stephanie van Hoppe; Matthijs J. van H...; Roeland E. Wasmann; Manoe J. Janssen; Alfred H. Schinkel; Rosalinde Masereeuw; Jos H. Beijnen; Rolf W. Sparidans
• Keywords: Cysteine Metabolism

Summary Ibrutinib is a first-in-class Bruton’s kinase inhibitor used in the treatment of multiple lymphomas. In addition to CYP3A4-mediated metabolism, glutathione conjugation can be observed. Subsequently, metabolism conjugates and finally their excretion feces urine occurs. These metabolites, however, reach substantial concentrations human subjects, especially when CYP3A4 inhibited. has unexplained nephrotoxicity high metabolite are also found kidneys Cyp3a knockout mice. Here, mechanism proposed where intermediate cysteine bioactivated. The ibrutinib through this cycle was confirmed cultured renal proximal tubule cells. Ibrutinib-mediated toxicity enhanced in-vitro by inhibitors breast cancer resistance protein (BCRP), P-glycoprotein (P-gp) multidrug (MRP). This result accumulating levels due efflux inhibition. Finally, inhibition downstream it shown now that direct responsible for toxicity.