Interindividual variability in CYP3A-mediated venetoclax metabolism in vitro and in vivo in patients with chronic lymphocytic leukemia.

ABSTRACT: Venetoclax is a first-in-class orally administered B-cell lymphoma-2 inhibitor used to treat chronic lymphocytic leukemia (CLL). Venetoclax is primarily metabolized in the liver by cytochrome P450 (CYP) 3A4 to its major metabolite M27, via M5, and M2, M3, and M4 via oxidation. Although venetoclax is a breakthrough in CLL treatment, managing drug safety and toxicity remains a clinical challenge. The objectives of this study were to investigate how individual CYP3A activity and protein expression affect hepatic venetoclax metabolism in vitro and examine whether plasma 4β-hydroxycholesterol (4β-HC)/cholesterol ratio can predict venetoclax metabolism in vitro and in vivo. In human liver microsomes (n = 20) and primary human hepatocytes (n = 15), venetoclax metabolite formation varied widely be

SUBMITTER: Lee J 

PROVIDER: S-EPMC11645475 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature