Deriving safe limits for N-nitroso-bisoprolol by error-corrected next-generation sequencing (ecNGS) and benchmark dose (BMD) analysis, integrated with QM modeling and CYP-docking analysis.

ABSTRACT: N-nitroso-bisoprolol (NBP) is a nitrosamine drug substance-related impurity (NDSRI) of bisoprolol, which is used to treat cardiac diseases since decades. To investigate the mutagenic potential of NBP, in vitro methods such as Enhanced Ames Test (EAT) and a mammalian cell gene mutation (HPRT) assay were used. To assess the in vivo mutagenicity, a 28-day repeat-dose study was conducted in wild-type NMRI mice, and liver and bone marrow samples were subjected to error-corrected next-generation sequencing (i.e., duplex sequencing) followed by benchmark dose analysis (BMD). NBP did not show mutagenic effects in Ames tests using 10 % and 30 % induced rat or 30 % uninduced hamster S9. However, relevant increases in mutation frequencies were observed in an EAT in the presence of 30 % induced hamste

SUBMITTER: Simon S 

PROVIDER: S-EPMC12454523 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature