title: Hypoxia/oxidative stress alters the pharmacokinetics of CPU86017-RS through mitochondrial dysfunction and NADPH oxidase activation.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Faculty of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Gao
authors.forename: Xuan-sheng
authors.initials: XS
authors.lastname: Ding
authors.forename: Yu-mao
authors.initials: YM
authors.lastname: Zhang
authors.forename: De-zai
authors.initials: DZ
authors.lastname: Dai
authors.forename: Mei
authors.initials: M
authors.lastname: Liu
authors.forename: Can
authors.initials: C
authors.lastname: Zhang
authors.forename: Yin
authors.initials: Y
authors.lastname: Dai
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006207:Half-Life; D006576:Heterocyclic Compounds, 4 or More Rings / Q000493:pharmacokinetics*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000889:Anti-Arrhythmia Agents; C000588615:CPU86017-RS; D006576:Heterocyclic Compounds, 4 or More Rings; D019255:NADPH Oxidases