Role Of Cytochrome P450 Isoforms Research Articles

Characterization of In Vitro and In Vivo Metabolism of Antazoline Using Liquid Chromatography-Tandem Mass Spectrometry.

Antazoline (ANT) was recently shown to be an effective and safe antiarrhythmic drug in the termination of atrial fibrillation. However, the drug is still not listed in clinical guidelines. No data on ANT metabolism in humans is available. We used liquid chromatography coupled with tandem mass spectrometry to identify and characterize metabolites of ANT. We analyzed plasma of volunteers following a single intravenous administration of 100 mg of ANT mesylate and in in vitro cultures of human hepatocytes. We revealed that ANT was transformed into at least 15 metabolites and we investigated the role of cytochrome P450 isoforms. CYP2D6 was the main one involved in the fast metabolism of ANT. The biotransformation of ANT by CYP2C19 was much slower. The main Phase I metabolite was M1 formed by the removal of phenyl and metabolite M2 with hydroxyl in the para position of phenyl. Glucuronidation was the leading Phase II metabolism. Further study on pharmacokinetics of the metabolites would allow us to better understand the activity profile of ANT and to predict its potential clinical applications. Ultimately, further investigation of the activity profile of the new hydroxylated M2 metabolite of ANT might result in an active substance with a different pharmacological profile than the parent molecule, and potentially a new drug candidate.

Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations

Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.

Antipsychotic Medication and Risk of QTc Prolongation: Focus on Multiple Medication and Role of Cytochrome P450 Isoforms

Objective: To identify the effects of antipsychotics on QTc prolongation in light of age, gender, antipsychotic combination pattern, antipsychotic doses and cytochrome P450 (CYP) mediation, using large database describing the antipsychotic treatment of patients with schizophrenia in Japan. Methods: Using database of 4176 patients with schizophrenia discharged between April 2004 and March 2005 and receiving outpatient treatment from 526 psychiatric hospitals in Japan. Of the patients, 1437 were included for the analysis. These patients were classified into three groups according to the antipsychotic CPZ-equivalent doses that they received (low, 1 - 299 mg; middle, 300 - 999 mg; and high, ≥1000 mg). QTc intervals ≥ 440 msec were considered prolonged. We reviewed all the package inserts of the antipsychotics used from the website of Pharmaceuticals and Medical Devices Agency. Results: The mean QTc interval of the total patient group was 410.4 ± 23.3 msec. The females had significantly higher QTc values than the males (414.5 ± 24.0 vs. 406.8 ± 22.2 msec, respectively; p 0.05). Logistic regression analysis revealed that female gender (odds ratio [OR] = 1.83; 95% CI: 1.28 - 2.56), CYP3A4-metabolized drugs (OR 1.56; 95% CI: 1.05 - 2.30) were associated with an increased risk of QTc prolongation. Conclusion: The co-prescription of CYP3A4-mediated antipsychotic drugs should be carefully considered in females due to potential risk of QTc prolongation. Further studies of the cardiovascular safety of antipsychotics are warranted in patients receiving multiple medications.

Pharmacogenetics of Clozapine: In Vivo Role of Cytochrome P450 Isoforms and P-Glycoprotein

Pharmacogenetics of Clozapine: In Vivo Role of Cytochrome P450 Isoforms and P-Glycoprotein

Role of Cytochrome P450 Isoforms in the Metabolism of Abamectin and Ivermectin in Rats

Abamectin (AVM) and ivermectin (IVM) are each metabolized by rat liver microsomes to 3‘‘-O-desmethyl (3‘‘-ODMe), 24-hydroxymethyl (24-OHMe), and 26-hydroxymethyl (26-OHMe) derivatives. Microsomes f...