Generation of statin drug metabolites through electrochemical and enzymatic oxidations
| Autor: | Smriti Khera, Na Hu |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Drug
Simvastatin Magnetic Resonance Spectroscopy Statin medicine.drug_class media_common.quotation_subject Oxidative phosphorylation Pharmacology Biochemistry Mass Spectrometry Analytical Chemistry Cytochrome P-450 Enzyme System polycyclic compounds medicine Lovastatin media_common chemistry.chemical_classification Anticholesteremic Agents nutritional and metabolic diseases Electrochemical Techniques Enzyme chemistry Mutation Toxicity lipids (amino acids peptides and proteins) Hydroxymethylglutaryl-CoA Reductase Inhibitors Oxidation-Reduction Drug metabolism medicine.drug |
| Zdroj: | Analytical and Bioanalytical Chemistry. 405:6009-6018 |
| ISSN: | 1618-2650 1618-2642 |
| Popis: | The generation of key drug metabolites for the purpose of their complete structural characterization, toxicity testing, as well as to serve as standards for quantitative studies, is a critical step in the pharmaceutical discovery and development cycle. Here, we utilized electrochemistry/mass spectrometry for the detection and subsequent generation of six phase I metabolites of simvastatin and lovastatin. Both simvastatin and lovastatin are widely used for the treatment of hypercholesterolemia. There are known drug-drug interaction issues of statin therapy, and it has been suggested that the oxidative metabolites may contribute to the cholesterol-lowering effect of both statins. Of the known phase I metabolites of simvastatin and lovastatin, none are commercially available, and chemical means for the synthesis of a very few of them have been previously reported. Here, we report that electrochemical oxidation of less than 1 mg each of simvastatin and lovastatin led to the generation of three oxidative metabolites of each parent to allow complete nuclear magnetic resonance characterization of all six metabolites. The yields obtained by the electrochemical approach were also compared with incubation of parent drug with commercially available bacterial mutant CYP102A1 enzymes, and it was found that the electrochemical approach gave higher yields than the enzymatic oxidations for the generation of most of the observed oxidative metabolites in this study. |
| Databáze: | OpenAIRE |
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