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: Male; Cell Survival; Antineoplastic Agents; Kidney Tubules, Proximal; Mice; 03 medical and health sciences; SDG 3 - Good Health and Well-being; Piperidines; ATP Binding Cassette Transporter, Subfamily G, Member 2; Animals; Cytochrome P-450 CYP3A; Humans; Pharmacology (medical); Pharmacokinetics; ATP Binding Cassette Transporter, Subfamily B, Member 1; LC-MS/MS; Cells, Cultured; Aged; Pharmacology; Mice, Knockout; Preclinical Studies; 0303 health sciences; Bioactivation; Adenine; Ibrutinib; Acute Kidney Injury; Glutathione; Neoplasm Proteins; 3. Good health; Metabolism; Oncology; Glutathione cycle; Multidrug Resistance-Associated Proteins

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