The Degradation Product of Ramipril Is Potentially Carcinogenic, Genotoxic and Mutagenic

(1) Background: The aim of this study was to identify the degradation product ramipril (RAM) formed under dry air and verify its potential modes carcinogenicity. We intended check whether formation presence in final dosage forms could pose a cancer risk humans who are treated with RAM due cardiological indications. carcinogenicity compound evaluated respect two mechanisms: direct DNA-damage indirect toxicity, secondary forming mutagenic N-nitroso metabolites. (2) Methods: Firstly, forced ageing test conducted for pure order induce degradation. validated HPLC system used describe kinetic reaction. emerging impurity identified by HPLC-MS. In second stage, degradant predicted using structure-based assessment silico QSAR model, employing three endpoints: carcinogenicity, genotoxicity mutagenicity. third obtained results were experimentally verified. To prediction, vitro micronucleus assay employed. It enabled us assess DNA-damaging properties at high concentrations (as screening series) usually observed human blood (to mimic clinical scenario). mutagenicity an Ames carried out. designed so as detect mechanisms mutagenicity: one (for degradant) (via N-nitroso-metabolites formation). NAP test. (3) Results: mechanism first-order, rate constant k = 1.396 ± 0.133 × 10−5 s−1 (T 373 K), thus rapid. Energy activation 174.12 46.2 kJ/mol, entropy positive, reaction bimolecular favored; enthalpy 171.65 48.7 endothermic. Only formed, it diketopiperazine derivative (DKP). simulation that DKP be carcinogenic genotoxic, but result had only moderate reliability. also non-mutagenic prediction strong (endpoint score 0.2). confirmatory experiment suggested cytotoxic aneugenic concentration (0.22 mg/mL), evidenced three-fold increase micronuclei relative control (11.86:33.33%, p 0.0184). At physiologic concentrations, cytotoxicity did not occur. This means limited threshold mechanism. assessment, mutagenic, nitrosation induced base substitutions mutations bacteria TA100 following metabolic 4.5 mg/mL, confirming (4) Conclusions: rapidly cyclizes air. resides drugs administered patients. is potentially yet typically occurring blood, effect unlikely. exposure patients DKP, exceeding typical level standard dosing, lead development, safe must verified follow-up vivo experiments. Based on our results, impossible establish maximum dose humans. Furthermore, itself liable nitroso-metabolites vivo. Nitroso-derivatives mutagens their real-life impact further studies. Until out, should formulated manufacturers procedures minimize reduce carcinogenesis, since cause via independent when over dosing occurs, N-nitrosamine formation.