Time-dependent inhibition of CYP3A4- mediated midazolam metabolism by macrolide antibiotics in CYP3A4 genetic variants: Comparison with testosterone metabolism

Takeshi Akiyoshi, Rina Naitou, Ayuko Imaoka, Mitsue Miyazaki, F. Peter Guengerich, Katsunori Nakamura, Koujiro Yamamoto, Hisakazu Ohtani

Research output: Contribution to journalArticlepeer-review

Abstract

Objectives: The present study aimed to evaluate the effects of CYP3A4 genetic variation on the kinetics of mechanismbased inhibition (MBI) of both inhibitors using midazolam as a substrate for comparison with our previous study, as midazolam and testosterone have different binding sites. Background: The genetic variation of cytochrome P450 (CYP) 3A4 affects MBI, expressed as the maximum inactivation rate constant (kinact,max) and the inhibitor concentration required to achieve half-maximal inactivation (KI). We previously showed, using testosterone as a substrate, that the MBI kinetics of erythromycin and clarithromycin differ among CYP3A4 variants. Materials and methods: Midazolam 1'-hydroxylation inactivation profiles of erythromycin and clarithromycin were assessed using recombinant CYP3A4.1, .2, .7, .16, and .18 expressed in Escherichia coli. MBI parameters were calculated from changes in the inactivation rate constant (Δkobs) by the inhibitors. Results: Both inhibitors increased Δkobs value in a concentration- and preincubation time-dependent manner, and MBI kinetics differed among variants. Trends of differences in MBI parameters among variants were similar to those assessed using testosterone as a substrate; KI decreased for CYP3A4.7, and kinact,max decreased for CYP3A4.2, .7, and .16. Conclusion: The genetic variation of recombinant CYP3A4 affects the MBI profile of CYP3A4 by erythromycin and clarithromycin, while the influence of genetic variation was similarly observed regardless of substrates. Our findings are of clinical relevance because the residual enzyme activity of CYP3A4 in the presence of inhibitor was estimated to vary among genetic variants.

Original languageEnglish
Pages (from-to)745-782
Number of pages38
JournalInternational journal of clinical pharmacology and therapeutics
Volume59
Issue number12
DOIs
Publication statusPublished - 2021 Dec

Keywords

  • CYP3A4 genetic variants
  • clarithromycin
  • erythromycin
  • mechanismbased inhibition
  • time-dependent inhibition

ASJC Scopus subject areas

  • General Medicine

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