Nice work by Cheung and Colleagues.
Evaluation of the nitrosamine impurities of ACE inhibitors using computational, in vitro, and in vivo methods demonstrate no genotoxic potential
We are now seeing more and more NDSRI safety data come out. Lets keep it coming.
Thanks @jbercu for sharing… we provide visibility for 4,900+ members here in the community!
Including the abstract for context:
Abstract:
Evaluation and mitigation of the potential carcinogenic risks associated with nitrosamines in marketed pharmaceutical products are areas of interest for pharmaceutical companies and health authorities alike. Significant progress has been made to establish acceptable intake (AI) levels for N -nitrosamine drug substance-related impurities (NDSRIs) using SAR, however some compounds require experimental data to support derivation of a recommended AI. Many angiotensin-converting enzyme inhibitors, identified by the suffix “pril,” have secondary amines that can potentially react to form nitrosamines. Here we consider a structural assessment and metabolism data, coupled with comprehensive in vitro and in vivo (mouse) genotoxicity testing to evaluate this particular class of nitrosamines. N -nitroso ramipril and N -nitroso quinapril, both of which are predicted to have inhibited nitrosamine bioactivation due to steric hinderance and branching at the α-position were non-genotoxic in the in vivo liver comet assay and non-mutagenic in the in vivo Big Blue® mutation and duplex sequencing assays. Predicted metabolism along with in vitro metabolism data and quantum chemical calculations related to DNA interactions offer a molecular basis for the negative results observed in both in vitro and in vivo testing. These nitrosamines are concluded to be non-mutagenic and non-carcinogenic; therefore, they should be controlled according to ICH Q3B guidance. Furthermore, these results for N -nitroso ramipril and N -nitroso quinapril should be considered when evaluating the appropriate AI and control strategy for other structurally similar “pril” NDSRIs.
And it’s open access! Thanks for sharing @jbercu
Now is the time for HAs to set a class limit for all nitroso-ACE inhibitors as NMIs.
Raphy, Can you please help us understand bit better your proposal? Thx
EMA commendably used the negative TGR for nitroso-quinapril to read-across and define nitroso-lisinopril as a NMI. Now we have also nitroso-ramipril that is negative in the TGR. It is time now, as recommended in our paper, that all nitroso-ACE inhibitors ("prils) be considered NMI.
Thank you for sharing
Thank you for sharing @jbercu and Naiffer. I believe this article would trigger health agencies to revise the limit of nitrosamine derivatives of enalapril, ramipril to ICH Q3A/B limits.
It is appreciated that author is educating the importance of Duplex sequencing assay highlighting the complexities of TGR assay.
The only drawback is author used AMES test method instead of Enhanced AMES (EAT) test but I believe EAT was not established at the time of this study. @conudel thanks for your work and making it public.