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

Abstract

AIM:

Hypoxia/oxidative stress can alter the pharmacokinetics (PK) of CPU86017-RS, a novel antiarrhythmic agent. The aim of this study was to investigate the mechanisms underlying the alteration of PK of CPU86017-RS by hypoxia/oxidative stress.

METHODS:

Male SD rats exposed to normal or intermittent hypoxia (10% O2) were administered CPU86017-RS (20, 40 or 80 mg/kg, ig) for 8 consecutive days. The PK parameters of CPU86017-RS were examined on d 8. In a separate set of experiments, female SD rats were injected with isoproterenol (ISO) for 5 consecutive days to induce a stress-related status, then CPU86017-RS (80 mg/kg, ig) was administered, and the tissue distributions were examined. The levels of Mn-SOD (manganese containing superoxide dismutase), endoplasmic reticulum (ER) stress sensor proteins (ATF-6, activating transcription factor 6 and PERK, PRK-like ER kinase) and activation of NADPH oxidase (NOX) were detected with Western blotting. Rat liver microsomes were incubated under N2 for in vitro study.

RESULTS:

The Cmax, t1/2, MRT (mean residence time) and AUC (area under the curve) of CPU86017-RS were significantly increased in the hypoxic rats receiving the 3 different doses of CPU86017-RS. The hypoxia-induced alteration of PK was associated with significantly reduced Mn-SOD level, and increased ATF-6, PERK and NOX levels. In ISO-treated rats, the distributions of CPU86017-RS in plasma, heart, kidney, and liver were markedly increased, and NOX levels in heart, kidney, and liver were significantly upregulated. Co-administration of the NOX blocker apocynin eliminated the abnormalities in the PK and tissue distributions of CPU86017-RS induced by hypoxia/oxidative stress. The metabolism of CPU86017-RS in the N2-treated liver microsomes was significantly reduced, addition of N-acetylcysteine (NAC), but not vitamin C, effectively reversed this change.

CONCLUSION:

The altered PK and metabolism of CPU86017-RS induced by hypoxia/oxidative stress are produced by mitochondrial abnormalities, NOX activation and ER stress; these abnormalities are significantly alleviated by apocynin or NAC.

• Authors: Jie Gao, Xuan-sheng Ding, Yu-mao Zhang, De-zai Dai, Mei Liu, Can Zhang, Yin Dai
• Journal: Acta pharmacologica Sinica (Acta Pharmacol Sin) Vol. 34 Issue 12 Pg. 1575-84 (Dec 2013) ISSN: 1745-7254 [Electronic] United States
• PMID: 24122013 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Arrhythmia Agents
• CPU86017-RS
• Heterocyclic Compounds, 4 or More Rings
• NADPH Oxidases

Topics

• Animals
• Anti-Arrhythmia Agents (pharmacokinetics)
• Area Under Curve
• Chromatography, High Pressure Liquid
• Dose-Response Relationship, Drug
• Enzyme Activation
• Half-Life
• Heterocyclic Compounds, 4 or More Rings (pharmacokinetics)
• Male
• Microsomes, Liver (enzymology)
• NADPH Oxidases (metabolism)
• Oxidative Stress
• Rats
• Rats, Sprague-Dawley