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


RESULTS
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.


CONCLUSIONS
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.
Research Division of Pharmacology, China Pharmaceutical University, Nanjing, China.
Yu-Mao
YM
Zhang
Feng
F
Yu
De-Zai
DZ
Dai
Jie
J
Gao
Xiao-Dong
XD
Cong
Yin
Y
Dai
D000098:Acetophenones / Q000494:pharmacology*; D000818:Animals; D000880:Anthraquinones / Q000378:metabolism / Q000493:pharmacokinetics*; D000893:Anti-Inflammatory Agents / Q000378:metabolism / Q000493:pharmacokinetics; D001120:Arginine / Q000378:metabolism / Q000493:pharmacokinetics*; D004338:Drug Combinations; D059865:Endoplasmic Reticulum Stress; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology; D019255:NADPH Oxidases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013482:Superoxide Dismutase / Q000378:metabolism*
D000098:Acetophenones; D000880:Anthraquinones; D000893:Anti-Inflammatory Agents; D004338:Drug Combinations; D004791:Enzyme Inhibitors; C576350:argirein; D001120:Arginine; C056165:acetovanillone; D013482:Superoxide Dismutase; D019255:NADPH Oxidases; C020491:rhein
argirein; endoplasmic stress; mitochondria; pharmacokinetics; rhein