Hypoxia alters pharmacokinetics of argirein because of mitochondrial dysfunction that is alleviated by apocynin

• Published in: Journal of pharmacy and pharmacology 2013-09, Vol.65 (9), p.1360-1372
• Main Authors: Zhang, Yu-Mao, Yu, Feng, Dai, De-Zai, Gao, Jie, Cong, Xiao-Dong, Dai, Yin
• Format: Article
• Language: English
• Subjects: Acetophenones - pharmacology; Animals; Anthraquinones - metabolism; Anthraquinones - pharmacokinetics; Anti-Inflammatory Agents - metabolism; Anti-Inflammatory Agents - pharmacokinetics; Arginine - metabolism; Arginine - pharmacokinetics; argirein; Drug Combinations; Endoplasmic Reticulum Stress; endoplasmic stress; Enzyme Inhibitors - pharmacology; Hypoxia - metabolism; Male; mitochondria; Mitochondria - enzymology; Mitochondria - pathology; NADPH Oxidases - metabolism; pharmacokinetics; Rats; Rats, Sprague-Dawley; rhein; Superoxide Dismutase - metabolism
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/jphp.12098

Objectives Pharmacokinetics (PK) of argirein might be changed in response to mitochondrial (MITO) dysfunction and activated nicotinamide adenine dinucleotide phosphate oxidase (NOX) on hypoxia. We hypothesized that hypoxic changes in MITO and NOX could alter PK and tissue distribution of argirein. We tested if these changes in PK of argirein by hypoxia could be relieved by apocynin (APO), a blocker of NOX, through normalizing MITO and NOX. Methods Male Sprague‐Dawley rats were exposed to hypoxia (O2 10% ± 5% 8 h per day) for 7 days and treated with APO (80 mg/kg, i.g.) in the last 4 days. The PK and tissue distribution of argirein were monitored by measuring its main metabolite rhein using HPLC analysis. Manganese superoxide dismutase (MnSOD) and NOX were assayed. Key findings The PK parameters and concentrations of rhein in the kidney, liver, heart and testes were significantly altered under hypoxia, accompanied with a reduced MnSOD and upregulated NOX compared with the normal. Altered argirein PK and distribution in these organs were relieved following APO administration. Conclusion Abnormal PK and distribution of argirein by assaying its metabolite rhein are significant, consequent to hypoxic injury that is significantly ameliorated by APO through normalizing MITO and NOX.