Foundational Research On The Effect Of Pharmacokinetics Of Drugs At High Altitude Environment

After People enter the high altitude within several hours, the body will produce a series of physiological changes. The body’s reaction will changes of absorption, distribution, metabolism and excretion of drugs. In other words, the hypoxia and low pressure of high altitude environment will affect pharmacokinetic (PK) of drugs in vivo. So it’s important to comparison PK at different conditions. Aminophylline, buspirone, furosemide, methazolamide, propranolol and metoprolol are used as prophylactic treatment for altitude disease or commonly drugs at high ailitude. Although the PK study for the drugs have been reported previously under normal conditions, the PK study at high altitude has not been reported. The paper is to report the PK of drugs in rats living at low altitude and after acute exposure to high altitude, and research the related mechanism from blood gas and the plasma protein binding ratio.The wistar rats were randomly divided into Plain group (P), high altitude group (H), blank group of Plain (A) and blank group of high altitude (B). Drugs were intragastric administered to rats in low altitude (50m) and exposure to high altitude (4010m) groups:The rats of P group residing at low altitude, and the rats of H group exposure to high altitude. Blood samples were collected from veins of eye socket into heparinized centrifuge tubes at0,0.33,0.66,1,1.5,2,3,4,6,8,12,24hours of aminophylline, buspirone, furosemide, methazolamide and propranolol, and at0,0.083,0.25,0.5,0.75,1,1.5,2,4,6,8,12and24hours of metoprolol after study drug administration. Altrafiltrate of plasma and plasma concentration of drugs was determined by LC-MS/MS. Collected blood from the abdominal aorta of the rats of A group at low altitude and B group exposure to high altitude for blood gas analysis use automatic blood gas system.The SaO2, PaO2and PaCO2of group B were significantly reduced compare with group A, the cNa+and cCl-were significantly increased (P<0.05) compare with group A from results of blood gas analysis. Concentration of aminophylline, buspirone, furosemide and propranolol in plasma water decreased significantly after exposure to high altitude, therefore, the protein binding was significantly higher in the acute exposure to high altitude group compared with the low altitude group, the protein binding was higher in the H group compared with the P group of methazolamide and metoprolol, and no significant difference between two groups. After a single dose of intragastric administration, profiles of the concentration-time curves of aminophylline, buspirone and propranolol were best fitted to one-compartment model and furosemide, methazolamide and metoprolol were best fitted to two-compartment model. The PK parameters of H group was significantly different from that of P group. The Cmax and AUC were higher, The tl/2z and MRT were prolonged and the Clz/F was lower compared with the P group of buspirone, furosemide and propranolol. The parameters between two groups were significantly difference on statistics. The Tmax was lower and the other parameters were no variation of aminophylline. The t1/2β and tl/2a of parameters of compartmental model and AUC, Cmax, Clz/F of parameters of statistical moment were slightly changed and nonsense on statistics, and Tmax, tl/2z and MRT were higher of metoprolol, compared with the low group. The parameters of α, β, tl/2α, tl/2β of compartmental model and AUC, MRT, tl/2z, Tmax, Clz/F and Cmax of statistical moment of methazolamide were differents between two groups, and no statistically significant differences were observed.An LC-MS/MS method for determining the concentration of aminophylline, buspirone furosemide, methazolamide, propranolol and metoprolol in rats plasma were developed and applied to PK study. The method is simple, accurate, fast, sensitive and suitable for the PK study. Except for methazolamide, the metabolic processes of other drugs after acute exposure to high altitude were significantly different from that of plain area. And the effects of high altitude environment to different drugs of the same and different systems were different. The change of PK parameters were concerned with diversity of plasma protein binding ratio and blood gas, and also may be related to the activity of metabolic enzyme, the higher of blood viscosity, the category and states of animals. About detailed mechanism need to investigate in the next experiments. This study found significant changes in the disposition of drugs in these rats after acute exposure to high altitude, which could be of therapeutic importance. This finding may provide valuable references and fundament of experiments for PK of human after acute exposure to high altitude.