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<p>Cytochrome P450 3A (CYP3A) enzymes metabolize many clinically important drugs. Previously, we clarified that bardoxolone methyl (BX), an Nrf2 activator, decreased CYP3A mRNA expression level in HepG2 cells. However, its effects on hepatic CYP3A protein and <i>in vivo</i> drug disposition remained unclear. This study investigated whether BX downregulates hepatic CYP3A expression and activity, and determine its impact on the pharmacokinetics of midazolam (MDZ), involving atypical substrate probing for CYP3A, in rats.　Male Sprague-Dawley rats received a single intraperitoneal dose of BX (10&#xa0;mg/kg). BX decreased hepatic CYP3A mRNA and protein levels, and V<sub>max</sub> value for MDZ hydroxylation without altering the K<sub>m</sub> value. Intravenous MDZ pharmacokinetics (5&#xa0;mg/kg) were unaffected following BX treatment; however, oral administration (15&#xa0;mg/kg) showed reduced apparent clearance (CL<sub>tot</sub>/F), a measure of inherent <i>in vivo</i> metabolic capacity, leading to increases in AUC and bioavailability. No significant alterations in liver weight or plasma hepatic markers were observed. In conclusion, we suggest that hepatic CYP3A expression and intrinsic metabolic capacity are suppressed by BX, thereby markedly increasing the oral bioavailability of CYP3A substrates. These findings may help in the early detection of clinically significant drug interactions between Nrf2 activators and CYP3A substrate drugs.</p>

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Downregulation of hepatic CYP3A isoforms by bardoxolone methyl in rats and its impact on in vivo metabolic capacity reflecting pharmacokinetics

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月28日

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  • Yuichiro Hori,
  • Shuhei Fukuno,
  • Hiroki Shirane,
  • Rei Watanabe,
  • Kyotaro Murata,
  • Mei Takenaka,
  • Hiroki Konishi,
  • Katsuhito Nagai

摘要

Cytochrome P450 3A (CYP3A) enzymes metabolize many clinically important drugs. Previously, we clarified that bardoxolone methyl (BX), an Nrf2 activator, decreased CYP3A mRNA expression level in HepG2 cells. However, its effects on hepatic CYP3A protein and in vivo drug disposition remained unclear. This study investigated whether BX downregulates hepatic CYP3A expression and activity, and determine its impact on the pharmacokinetics of midazolam (MDZ), involving atypical substrate probing for CYP3A, in rats.　Male Sprague-Dawley rats received a single intraperitoneal dose of BX (10 mg/kg). BX decreased hepatic CYP3A mRNA and protein levels, and Vmax value for MDZ hydroxylation without altering the Km value. Intravenous MDZ pharmacokinetics (5 mg/kg) were unaffected following BX treatment; however, oral administration (15 mg/kg) showed reduced apparent clearance (CLtot/F), a measure of inherent in vivo metabolic capacity, leading to increases in AUC and bioavailability. No significant alterations in liver weight or plasma hepatic markers were observed. In conclusion, we suggest that hepatic CYP3A expression and intrinsic metabolic capacity are suppressed by BX, thereby markedly increasing the oral bioavailability of CYP3A substrates. These findings may help in the early detection of clinically significant drug interactions between Nrf2 activators and CYP3A substrate drugs.