ArticleDrug metabolism and disposition: the biological fate of chemicals2015
P450-Based Drug-Drug Interactions of Amiodarone and its Metabolites: Diversity of Inhibitory Mechanisms.
Article in Drug metabolism and disposition: the biological fate of chemicals, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 58 citations in OpenAlex.
- Risk of Severe Hypoglycemia Associated With Concomitant Use of Sulfonylureas and Amiodarone.Diabetes, obesity & metabolism · 2026Article
- Pharmacokinetics in the Fontan circulation: a multi-organ puzzle.European heart journal. Cardiovascular pharmacotherapy · 2026Review
- The nematode Caenorhabditis elegans has a cationic amphiphilic drug (CAD) defense system.PLoS biology · 2026Article
- Device Interrogation Unmasking Flecainide-Induced Wide Complex Tachycardia.JACC. Case reports · 2026Article
- Role of metabolites in drug-drug interactions.Drug metabolism and pharmacokinetics · 2026Review
- The Role of Clinical Pharmacogenetics and Opioid Interactions in Pain Management: Current Evidence and Future Perspectives.Pharmaceutics · 2026Review
- Real-World Impact of Amiodarone on Apixaban Population Pharmacokinetics in Hospitalized Patients.Clinical and translational science · 2025Article
- Lomitapide response in a cohort of patients with homozygous familial hypercholesterolemia and the potential influence of MTTP gene variants.Orphanet journal of rare diseases · 2025Article
- Rapidly Fatal Multiple Organ Failure of Intravenous Amiodarone: A Case Report and Literature Review.Clinical case reports · 2025Article
- Amiodarone and Ravuconazole Combination Potentiates Chemotherapy against Drug-Resistant Trypanosoma cruzi Strains.ACS omega · 2025Article
- Amiodarone extraction by continuous renal replacement therapy: results from an ex vivo study.Journal of artificial organs : the official journal of the Japanese Society for Artificial Organs · 2025Article
- The strong clinical interaction between bupropion and CYP2D6 is primarily mediated through bupropion metabolites and their stereoisomers: A paradigm for evaluating metabolites in drug-drug interaction risk.Drug metabolism and disposition: the biological fate of chemicals · 2025Article
- Innovative Epicardial Bigels Containing Amiodarone Hydrochloride: Pharmacotechnical and Analytical Characterization.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Co-Administration of Amiodarone Increases Bleeding by Affecting Rivaroxaban Pharmacokinetics in Patients with Atrial Fibrillation.Pharmaceutics · 2024Article
- A Review of CYP-Mediated Drug Interactions: Mechanisms and In Vitro Drug-Drug Interaction Assessment.Biomolecules · 2024Review
- Observational
- Challenges and Opportunities in P450 Research on the Eye.Drug metabolism and disposition: the biological fate of chemicals · 2023Review
- Desipramine induces eryptosis in human erythrocytes, an effect blunted by nitric oxide donor sodium nitroprusside and N-acetyl-L-cysteine but enhanced by Calcium depletion.Cell cycle (Georgetown, Tex.) · 2023Article
- Green electrosynthesis of drug metabolites.Toxicology research · 2023Review
- Colchicine Drug Interaction Errors and Misunderstandings: Recommendations for Improved Evidence-Based Management.Drug safety · 2023Review
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Authors and funding
3 authors at 1 institution in 1 country.
Funding
Abstract
In this study, IC50 shift and time-dependent inhibition (TDI) experiments were carried out to measure the ability of amiodarone (AMIO), and its circulating human metabolites, to reversibly and irreversibly inhibit CYP1A2, CYP2C9, CYP2D6, and CYP3A4 activities in human liver microsomes. The [I]u/Ki,u values were calculated and used to predict in vivo AMIO drug-drug interactions (DDIs) for pharmaceuticals metabolized by these four enzymes. Based on these values, the minor metabolite N,N-didesethylamiodarone (DDEA) is predicted to be the major cause of DDIs with xenobiotics primarily metabolized by CYP1A2, CYP2C9, or CYP3A4, while AMIO and its N-monodesethylamiodarone (MDEA) derivative are the most likely cause of interactions involving inhibition of CYP2D6 metabolism. AMIO drug interactions predicted from the reversible inhibition of the four P450 activities were found to be in good agreement with the magnitude of reported clinical DDIs with lidocaine, warfarin, metoprolol, and simvastatin. The TDI experiments showed DDEA to be a potent inactivator of CYP1A2 (KI = 0.46 μM, kinact = 0.030 minute(-1)), while MDEA was a moderate inactivator of both CYP2D6 (KI = 2.7 μM, kinact = 0.018 minute(-1)) and CYP3A4 (KI = 2.6 μM, kinact = 0.016 minute(-1)). For DDEA and MDEA, mechanism-based inactivation appears to occur through formation of a metabolic intermediate complex. Additional metabolic studies strongly suggest that CYP3A4 is the primary microsomal enzyme involved in the metabolism of AMIO to both MDEA and DDEA. In summary, these studies demonstrate both the diversity of inhibitory mechanisms with AMIO and the need to consider metabolites as the culprit in inhibitory P450-based DDIs.
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