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Hypoxia/oxidative stress alters the pharmacokinetics of CPU86017-RS through mitochondrial dysfunction and NADPH

Jie Gao1, Xuan-sheng Ding, Yu-mao Zhang

  • 1Faculty of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.

Acta Pharmacologica Sinica
|October 15, 2013
PubMed
Abstract

Insights

Hypoxia and oxidative stress alter antiarrhythmic CPU86017-RS pharmacokinetics by affecting mitochondrial function and increasing ER stress. Apocynin or N-acetylcysteine (NAC) can reverse these effects.

Area of Science:

  • Pharmacology
  • Cardiovascular Research
  • Biochemistry

Background:

  • Hypoxia and oxidative stress can significantly impact drug pharmacokinetics (PK).
  • CPU86017-RS is a novel antiarrhythmic agent whose PK may be affected by these conditions.
  • Understanding these alterations is crucial for effective therapeutic use.

Purpose of the Study:

  • To investigate the mechanisms by which hypoxia/oxidative stress alter the PK of CPU86017-RS.
  • To identify potential therapeutic interventions to mitigate these changes.

Main Methods:

  • Male and female Sprague-Dawley rats were exposed to hypoxia or isoproterenol (ISO) to induce stress.
  • CPU86017-RS was administered, and PK parameters and tissue distribution were analyzed.
  • Levels of key proteins involved in oxidative stress (Mn-SOD, NOX) and ER stress (ATF-6, PERK) were measured.
  • In vitro studies using liver microsomes assessed drug metabolism.

Main Results:

  • Hypoxia significantly increased CPU86017-RS Cmax, t1/2, MRT, and AUC, associated with reduced Mn-SOD and increased ER stress markers and NOX.
  • ISO-induced stress increased CPU86017-RS tissue distribution and NOX levels.
  • Apocynin (NOX blocker) and N-acetylcysteine (NAC) reversed the PK and distribution abnormalities.
  • In vitro metabolism of CPU86017-RS was reduced under hypoxic conditions and restored by NAC.

Conclusions:

  • Hypoxia/oxidative stress alter CPU86017-RS PK and metabolism via mitochondrial dysfunction, NOX activation, and ER stress.
  • Apocynin and NAC effectively alleviate these stress-induced abnormalities.
  • These findings suggest strategies to manage CPU86017-RS therapy in patients experiencing hypoxia or oxidative stress.

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