Synthesis and evaluation of nevirapine analogs to study the metabolic activation of nevirapine

Yasuhiro Tateishi, Tomoyuki Ohe, Daisuke Yasuda, Kyoko Takahashi, Shigeo Nakamura, Yasuhiro Kazuki, Tadahiko Mashino

Research output: Contribution to journalArticle

Abstract

Nevirapine (NVP) is widely used as a non-nucleoside reverse transcriptase inhibitor of HIV-1, however, it is associated with severe skin and liver injury. The mechanisms of these adverse reactions are not yet clear, but the metabolic activation of NVP is thought to be related to the injury process. Until now, several metabolic activation pathways of NVP have been reported. In this study, in order to identify the reactive metabolite of NVP mainly responsible for CYP inhibition and liver injury, we synthesized five NVP analogs designed to avoid the proposed bioactivation pathway and evaluated their metabolic stabilities, CYP3A4 time-dependent inhibitory activities, and cytotoxicity. As a result, only a pyrimidine analog of NVP, which could avoid the formation of a reactive epoxide intermediate, did not inhibit CYP3A4. Outside of this compound, the other synthesized compounds, which could avoid the generation of a reactive quinone-methide intermediate, inhibited CYP3A4 equal to or stronger than NVP. The pyrimidine analog of NVP did not induce cytotoxicity in HepG2 and transchromosomic HepG2 cells, expressing major four CYP enzymes and CYP oxidoreductase. These results indicated that the epoxide intermediate of NVP might play an important role in NVP-induced liver injury.

Original languageEnglish
Pages (from-to)238-243
Number of pages6
JournalDrug Metabolism And Pharmacokinetics
Volume35
Issue number2
DOIs
Publication statusPublished - 2020 Apr

Keywords

  • Cytochrome P450
  • HepG2
  • Hepatotoxicity
  • Metabolic activation
  • Nevirapine

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science
  • Pharmacology (medical)

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