Changes Of Pharmacokinetic Influence Factors After Acute Exposure To High Altitude

Objectives:1.To study the changes of blood gas index, biochemical indicators，pathologicalchanges of the body’s major organs and P450enzyme activity after acute exposure to highaltitude at4010meters from55m in rats, and to explore its effects on thepharmacokinetics.2.To observe the effects of acute exposure to high altitude at4010meters from55m onpharmacokinetics of propranolol and furosemide in rats, and to investigate the causes of thechange and its significance of rational drug use in high altitude.Methods:1.28healthy male Wistar rats were randomly divided into4groups, group A is thecontrol group in plain area, and B were acutely exposed to high altitude. Group A and B which had no drug administration were used for blood gas, biochemical indicators, P450enzyme activity and pathological changes research, while group C and D were used forpharmacokinetics determination of Propmnolol and furosemide at high altitude.2.Animals arrived the zhongchuan airport by air transport,then transport the rats to theplateau by van with air conditioning immediately, all the animals were fed Teklad CertifiedRodent Diet and jelly for water replacement in the process of air transport, while tap water inthe process of van transport.3.Blood gas analysis is carried out immediately with automatic blood gas system（RADIOMETER ABL80） by collected1ml aorta blood from the abdominal aorta，andmaking a contrast between plain area and high altitude.4.Blood was collected from vena orbitalis posterior in centrifuge tubes, which containedheparin sodium. The samples were centrifuged at room temperature and then detected thebiochemical indicators with automatic biochemistry analyzer, and making a contrast betweenthe plain area and high altitude.5.Heart,cerebrum, lungs, liver and kidneys were completely gathered and then stainedwith hematoxylin-eosin. Pathological changes were observed under microscope.6.Liver microsome were extracted with the use of differential centrifugation, theactivity of CYP1A2and3A4were detected with using light-emitting assay byGloMax20/20luminometer luminescence detector, and making a contrast between plain area andhigh altitude.7.Pharmacokinetic research did in the plain area and in the high altitude again after acleaning period of7days in the same rat. The content of propranolol and furosemide weredetected by LC-MS/MS, and using the DAS （Drug and Statistics）2.0software to calculatethe pharmacokinetic parameters, and making a contrast between the plain area and highaltitude.8. After oral administration of Propranolol to the rats through gavage for3days whenthe rats arrived at high altitude, and detected the blood gas indexs in the third day. Toobserve the affects of Propranolol on blood gas indexs.Results: 1.Blood gas Analytic results show that BB、BE、pCO₂、sO₂、pO₂severely increasedby20times,13.5times,32.03%,8.25%,44.28%respectively after acute exposure to highaltitude, while Hct，Hb，cNa+，cCl-significantly decreased by23.01%,23.37%,3.41%,13.55%,all the results was considered to be statistically significant（p＜0.05）.2.Biochemical indicators results show that AST、ALT、TBIL、ALP、CK、LHD、UA、GLU severely increased by48.50%,47.90%,19.35times,103.02%,66.15%,4.64times,74.72%,22.42%respectively after acute exposure to high altitude, TP decreased by17.80%, all the results was considered to be statistically significant（p＜0.05）.3.Pathological shows that heart, brain, lung, liver, kidney had varying degrees ofdamage. We can see that myocardial cell fibers arranged disorder, inflammatoryinfiltration, brain neurons are edematous while perivascular space occurred, and neuronsof seahorse are metamorphic and karyopyknotic,alveolar wall is hyperemic, edematousand incrassate, alveolus epithelium becomes hyperplastic while neutrophilic granulocytesinfiltrate, the central vein of liver are edematous and karyopyknotic Mesangial cells arehyperplastic in glomerulus tissue.4.The activity of CYP1A2and3A4were diminished by96.56%and43.53%respectively after acute exposure to high altitude of4010m.5.The pharmacokinetics of propranolol significantly changed,t_1/2α,AUC,MRT,t_1/2, andC_maxincreased significantly by42.92%,421.00%,47.45%,62.68%and352.96%respectively,CL and V decreased by80.87%and68.94%respectively after acute exposure to highaltitude at4010meters, the pharmacokinetics of furosemide are also significantly changed,t_1/2,Kα,AUC,MRT,t_1/2and C_maxincreased significantly by252.66%,69.04%,111.41%,117.75%and67.95%,Tmax and CL decreased by34.61%and52.23%respectively.6.Blood gas indexs were significantly changed when after oral administration ofPropranolol through gavage when the rats arrived at high altitude, pO₂,sO₂,BB,BE andcCa2+increased by27.43%,6.4%,68.93%,63.33%and14.15%respectively，AG, cNa+andctHb decreased by47.55%,3.86%and27.39%.Conclusions:1. Blood gas index of rats were significantly changed after acute exposure to high altitude. The results show that the pO₂、sO₂significantly decreased, and the pH is notchanged, the body is in the compensatory phase of metabolic acidosis, bloodconcentrated by water loss. All the results could affect the absorption and distribution ofdrugs, and the high concentrations of blood c may make the blood flow through the liverand kidney tissue slowly, and decreased the drugs that flow through the liver and kidneytissue per unit time or per unit volume, and the elimination rate of drug in the body mayaffected by it.2.Biochemical index of the rats were significantly changed after acute exposure tohigh altitude. This may prompt that the myocardial, liver and kidney function weredamaged,then it will affect the distribution, metabolism and excretion of drugs, andresult in increased drug concentration, longer half-life and reduced drug clearance.3.Pathological shows that heart, brain, lung, liver, kidney had varying degrees ofdamage which will affects the absorption and distribution of drugs, metabolism andexcretion.4.The activity of CYP1A2and3A4were significantly diminished by after acuteexposure to high altitude of4010m, CYP1A2and3A4are the main part of the liver,1A2account for13%of the total liver, and involving the metabolism about20drugs （includingpropranolol）.3A4account for30%of the liver, involving the metabolism about150drugs in38sorts, so the drug metabolism and excretion may significantly slow down afteracute exposure to high altitude.5.The pharmacokinetics of propranolol and furosemide were significantly changed,We should reduce the dosage or extend the dosing interval in high altitude to maintain thedrug concentration in therapeutic window since velocity of metabolism and excretion arereduced.6. Propranolol has great improvement for blood gas index in the high altitude, it isworthy for further study because of its effects in resisting hypoxia.