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Extrahepatic metabolism of ibrutinib.
Invest New Drugs. 2020 Jul 04 [Online ahead of print]IN

Abstract

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 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.

Authors+Show Affiliations

Division of Pharmacoepidemiology & Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. Benu apotheek Hoorn, Pakhuisstraat 80, 1621 GL, Hoorn, The Netherlands.Division of Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. Charles River Laboratories, Darwinweg 24, 2333 CR, Leiden, The Netherlands.Division of Chemical Biology & Drug Development, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. Institute of Biology, Biological Chemistry Group, Leiden University, Sylviusweg 72, 2333 BE, Leiden, The Netherlands.Department of Pharmacy, Radboud University Medical Centre, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Observatory, Cape Town, 7925, South Africa.Division of Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.Division of Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.Division of Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands.Division of Pharmacoepidemiology & Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. Department of Clinical Pharmacology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands.Division of Pharmacoepidemiology & Clinical Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. R.W.Sparidans@uu.nl. Division of Pharmacology, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. R.W.Sparidans@uu.nl. Division of Chemical Biology & Drug Development, Faculty of Science, Department of Pharmaceutical Sciences, Utrecht University, Universiteitsweg 99, 3584 CG, Utrecht, The Netherlands. R.W.Sparidans@uu.nl.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32623551

Citation

Rood, Johannes J M., et al. "Extrahepatic Metabolism of Ibrutinib." Investigational New Drugs, 2020.
Rood JJM, Jamalpoor A, van Hoppe S, et al. Extrahepatic metabolism of ibrutinib. Invest New Drugs. 2020.
Rood, J. J. M., Jamalpoor, A., van Hoppe, S., van Haren, M. J., Wasmann, R. E., Janssen, M. J., Schinkel, A. H., Masereeuw, R., Beijnen, J. H., & Sparidans, R. W. (2020). Extrahepatic metabolism of ibrutinib. Investigational New Drugs. https://doi.org/10.1007/s10637-020-00970-x
Rood JJM, et al. Extrahepatic Metabolism of Ibrutinib. Invest New Drugs. 2020 Jul 4; PubMed PMID: 32623551.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Extrahepatic metabolism of ibrutinib. AU - Rood,Johannes J M, AU - Jamalpoor,Amer, AU - van Hoppe,Stephanie, AU - van Haren,Matthijs J, AU - Wasmann,Roeland E, AU - Janssen,Manoe J, AU - Schinkel,Alfred H, AU - Masereeuw,Rosalinde, AU - Beijnen,Jos H, AU - Sparidans,Rolf W, Y1 - 2020/07/04/ PY - 2020/06/09/received PY - 2020/06/24/accepted PY - 2020/7/6/entrez PY - 2020/7/6/pubmed PY - 2020/7/6/medline KW - Bioactivation KW - Glutathione cycle KW - Ibrutinib KW - LC-MS/MS KW - Metabolism KW - Pharmacokinetics JF - Investigational new drugs JO - Invest New Drugs N2 - 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 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. SN - 1573-0646 UR - https://www.unboundmedicine.com/medline/citation/32623551/Extrahepatic_metabolism_of_ibrutinib L2 - https://doi.org/10.1007/s10637-020-00970-x DB - PRIME DP - Unbound Medicine ER -
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