| As the vigorous development of aerospace engineering, protection of astronauts has become an issue of concern in the world. There are many factors in space environment,such as strong radiation, noise, shock, vacum, microgravity, etc. All of these factors can affect the health of astronauts. Microgravity can influence the pharmacokinetics. The changes of pharmacokinetics may affect the safety of drug application in microgravity, and even have an increased risk of adverse effects. It is dangerous to use medication under normal gravity for microgravity. Therefore, it is critical to study the mechanism of pharmacokinetics under microgravity.There are many factors affecting pharmacokinetics, such as gastric emptying,gastrointestinal metabolism, gastrointestinal blood flow rate, drug efflux, lymph circulation,etc. Weightlessness was simulated by tail suspension of rats. This study aims to explore the effect of simulated weightlessness on rat P-gp expression and pharmacokinetic study of GA.The results showed that the expressions of P-gp in brain of rats under simulated weightlessness for 3 days and 7 days were lower than that under normal gravity, but there were no significant differences in quantity of expressions; The expressions of P-gp in brain of rats under simulated weightlessness for 14 days and 21 days showed an increasing trend,and the quantity of expressions increased by 24 %(14 days) and 25 %(21 days)respectively. The P-gp activities in brain of rats under both short-term and long-term simulated weightlessness were decreased in different degrees. There was significant difference in activity between normal gravity and microgravity 3 days(p<0.05). The expressions of mdr 1 were significantly increased(p<0.01) in brain of rats under simulated weightlessness for 14 days, and the quantity of mdr 1 was 2.5 times that of normal gravity.This was consistent with the trend of protein expression in brain tissue. The quantity of mdr1 gene in brain of rats under simulated weightlessness for 3 days and 7 days were increased by 105 %(p<0.01) and 62 %(p<0.05) respectively. The expression of mdr 1 in brain tissue of rats under simulated weightlessness for 21 days was decreased, but there was no significant difference in quantity of mdr 1.A sensitive ultra high performance liquid chromatography tandem mass spectrometry(UHPLC-MS) method was developed for determination of GA in rat plasma, urine, bile and main tissues. This validated method was firstly applied to pharmacokinetics, excretion and tissue distribution in rats. The AUC(0-T) in rats were 580.9 ± 86.8 μg h/L(4 mg/kg, iv), 14.7± 5.7 μg h/L(40 mg/kg, po) and 37.0 ± 12.1 μg h/L(80 mg/kg, po), respectively. The BA of GA in rats were 0.25 %(40 mg/kg) and 0.32 %(80 mg/kg), respectively. GA rapidly distributed to tissues after administration, of which the largest distribution in liver tissue,followed by lung, kidney, heart, spleen and the minimum distribution in brain. The distribution of GA in the liver and brain increased initially then decreased. The distribution of GA in heart and spleen tissues increased gradually after administration. GA distributed quickly to the lung and kidney tissues and decreased with dosing time prolonged. GA reached the cumulative excretion amount of 25.3 ± 1.7 μg in bile at 24 h post dosing and0.275 ± 0.08 μg in urine at 60 h post dosing. The excretion of GA in urine amounted to only0.003 ± 0.001 ‰ of the dosage within 60 h after dosing and in bile to 3.16 % with in 24 h after dosing.In summary, this study has been explored the effects of simulated weightlessness on P-gp expression, P-gp activity and mdr 1 expression. A sensitive UHPLC-MS/MS has been developed for determination of GA in rat plasma, urine, bile and main tissues. The present study firstly reported pharmacokinetic, excretion and distribution of GA in rats after oral administration. These findings would be helpful for clinical use of GA. The pharmacokinetic study of GA in rats under simulated weightlessness remains to be further explored. |
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