Pharma / Biotech

Extrahepatic metabolism of ibrutinib.




Icon for Springer

Extrahepatic metabolism of ibrutinib.

Invest New Drugs. 2020 Jul 04;:

Authors: Rood JJM, Jamalpoor A, van Hoppe S, van Haren MJ, Wasmann RE, Janssen MJ, Schinkel AH, Masereeuw R, Beijnen JH, Sparidans RW

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.

PMID: 32623551 [PubMed - as supplied by publisher]

Source link








Related posts

IMIQUIMOD Powder [Attix Pharmaceuticals Inc]

Newsemia

Effects of Rifamycin Coadministration on Bedaquiline Desmethylation in Healthy Adult Volunteers.

Newsemia

Pharmacokinetic and pharmacodynamic of the cognitive enhancer modafinil: Relevant clinical and forensic aspects.

Newsemia

This website uses cookies to improve your experience. We'll assume you're ok with this, but you can opt-out if you wish. Accept Read More

Privacy & Cookies Policy