High-throughput cytochrome P450 loss and metabolic intermediate complex assays to aid in designing out of CYP3A inactivation.

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  • Author(s): Russell DA;Russell DA; Cerny MA; Cerny MA
  • Source:
    Methods in enzymology [Methods Enzymol] 2023; Vol. 690, pp. 341-368. Date of Electronic Publication: 2023 Sep 09.
  • Publication Type:
    Journal Article; Research Support, N.I.H., Extramural
  • Language:
    English
  • Additional Information
    • Source:
      Publisher: Academic Press Country of Publication: United States NLM ID: 0212271 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-7988 (Electronic) Linking ISSN: 00766879 NLM ISO Abbreviation: Methods Enzymol Subsets: MEDLINE
    • Publication Information:
      Original Publication: New York, Academic Press.
    • Subject Terms:
      Cytochrome P-450 CYP3A*/metabolism ; Cytochrome P-450 Enzyme Inhibitors*/pharmacology ; Cytochrome P-450 Enzyme Inhibitors*/metabolism; Cytochrome P-450 Enzyme System/metabolism ; Drug Interactions ; Heme/metabolism
    • Abstract:
      Time-dependent inactivation (TDI) of cytochrome P450 (CYP) enzymes may result in clinical drug-drug interactions (DDIs). Therefore, designing out of CYP TDI prior to advancing a compound to clinical development is highly desirable. As TDI of CYP3A is a common occurrence in small molecule drug discovery, high-throughput methods are sought to help identify the mechanism of inactivation and enable design strategies to mitigate CYP3A TDI. CYP inactivation via modification or destruction of the prosthetic heme group results in loss of the ability of the enzyme to bind carbon monoxide. Additionally, formation of a tight binding complex with the heme iron, referred to as a metabolic intermediate (MI) complex, also results in enzyme inactivation. The methods described herein provide a high-throughput means of identifying and comparing compounds for their ability to inactivate via destruction/modification of the heme via loss of the ability to bind carbon monooxide, as well as via formation of an MI complex.
      (Copyright © 2023. Published by Elsevier Inc.)
    • Grant Information:
      T32 GM007750 United States GM NIGMS NIH HHS
    • Contributed Indexing:
      Keywords: CYP3A4; Cytochrome P450; Drug–drug interaction; Inactivation; Inactivator; MI complex; Mechanism; P450 loss; Time-dependent inactivation
    • Accession Number:
      EC 1.14.14.1 (Cytochrome P-450 CYP3A)
      0 (Cytochrome P-450 Enzyme Inhibitors)
      9035-51-2 (Cytochrome P-450 Enzyme System)
      42VZT0U6YR (Heme)
    • Publication Date:
      Date Created: 20231020 Date Completed: 20231023 Latest Revision: 20231025
    • Publication Date:
      20240829
    • Accession Number:
      10.1016/bs.mie.2023.08.002
    • Accession Number:
      37858534