Abstract
In this study, the phase I hepatic metabolism pathway of a cardiovascular drug nebivolol was proposed on the basis of a human liver microsomes assay with the use of LC-HR-MS coupled with the chemometric method. Six biotransformation products were found with the assistance of chemometric analysis. Five of them were identified as the previously reported products of alicyclic hydroxylation and dihydroxylation, aromatic hydroxylation, as well as alicyclic oxidation of the parent compound. Moreover, one metabolite, not reported so far, was found to be a product of N-dealkylation of nebivolol—2-amino-1-(6-fluoro-3,4-dihydro-2H-1-benzopyran-2-yl)ethan-1-ol. The novel metabolite was submitted to an in silico toxicity analysis to assess its biological properties. The applied computational methods indicated a significantly elevated risk of its mutagenic activity, compared to the parent molecule. Several metabolites of the nebivolol described in the literature were not detected in this study, indicating their non-hepatic origin.
Highlights
Drug metabolism studies are helpful in predicting the fate of a drug in the body and, in determining the appropriate drug dosage regimen
It should be noticed that the majority of the metabolic reactions are mainly catalyzed by cytochrome P450 enzymes, and this kind of research is often performed with the use of in vitro human liver microsomes (HLM) protocol [1,2,3,4,5,6]
We present the complete hepatic metabolism pathway of nebivolol established according to HLM assay with the use of LC-HR-MS coupled with chemometric method
Summary
Drug metabolism studies are helpful in predicting the fate of a drug in the body and, in determining the appropriate drug dosage regimen. The phase I reactions are decomposition processes including the introduction of polar groups (e.g., hydroxyl group) into the parent structure. These biotransformation reactions, based on redox processes, may lead to the formation of free radicals, which are highly reactive and might establish irreversible conjunctions with biological tissues, especially dangerous for living organisms (resulting in, e.g., cancerous processes). It should be noticed that the majority of the metabolic reactions are mainly catalyzed by cytochrome P450 enzymes, and this kind of research is often performed with the use of in vitro human liver microsomes (HLM) protocol [1,2,3,4,5,6]
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