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The Effect of Metformin and Hydrochlorothiazide on Cytochrome P450 3A4 Metabolism of Ivermectin: Insights from In Silico Experimentation.

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  • معلومة اضافية
    • المصدر:
      Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: Basel, Switzerland : MDPI, [2000-
    • الموضوع:
      Cytochrome P-450 CYP3A*/metabolism ; Metformin*/pharmacology ; Metformin*/metabolism ; Ivermectin*/pharmacology ; Ivermectin*/metabolism ; Drug Interactions* ; Hydrochlorothiazide*/pharmacology ; Hydrochlorothiazide*/metabolism; Humans ; Molecular Docking Simulation ; Computer Simulation ; Antiviral Agents/pharmacology ; Antiviral Agents/metabolism ; SARS-CoV-2/drug effects ; SARS-CoV-2/metabolism ; COVID-19 Drug Treatment
    • نبذة مختصرة :
      The spread of SARS-CoV-2 has led to an interest in using ivermectin (a potent antiparasitic agent) as an antiviral agent despite the lack of convincing in vivo clinical data for its use against COVID-19. The off-target prophylactic use of ivermectin adds a substantial risk of drug-drug interactions with pharmaceutical medications used to treat chronic conditions like diabetes and hypertension (metformin and hydrochlorothiazide, respectively). Therefore, this study aims to evaluate the potential drug-drug interactions between ivermectin with either metformin or hydrochlorothiazide. In silico experiments and high-throughput screening assays for CYP3A4 were conducted to understand how metformin and hydrochlorothiazide might affect CYP3A4's role in metabolizing ivermectin. The study findings indicated that hydrochlorothiazide is more stable than both ivermectin and metformin. This conclusion was further supported by root mean square fluctuation analysis, which showed that hydrochlorothiazide is more flexible. The variation in the principal component analysis scatter plot across the first three normal modes suggests hydrochlorothiazide has a more mobile conformation than ivermectin and metformin. Additionally, a strong inhibition of CYP3A4 by hydrochlorothiazide was observed, suggesting that hydrochlorothiazide's regulatory effects could significantly impede CYP3A4 activity, potentially leading to a reduced metabolism and clearance of ivermectin in the body. Concurrent administration of these drugs may result in drug-drug interactions and hinder the hepatic metabolism of ivermectin.
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    • Contributed Indexing:
      Keywords: COVID-19; SARS-CoV-2; cytochrome P450 3A4; diabetes; drug–drug interactions; hepatic metabolism; hydrochlorothiazide; hypertension; ivermectin; metformin
    • الرقم المعرف:
      EC 1.14.14.1 (Cytochrome P-450 CYP3A)
      9100L32L2N (Metformin)
      70288-86-7 (Ivermectin)
      0J48LPH2TH (Hydrochlorothiazide)
      EC 1.14.14.55 (CYP3A4 protein, human)
      0 (Antiviral Agents)
    • الموضوع:
      Date Created: 20241127 Date Completed: 20241127 Latest Revision: 20241130
    • الموضوع:
      20241202
    • الرقم المعرف:
      PMC11594981
    • الرقم المعرف:
      10.3390/ijms252212089
    • الرقم المعرف:
      39596155