Study On The Effect Of High Altitude Hypoxia On The Pharmacokinetics And Pharmacodynamics Of Atorvastatin

Dyslipidaemia is a serious risk factor for ASCVD.Atorvastatin is a widely used lipid-regulating drug in clinical practice,but the efficacy and adverse effects of atorvastatin vary widely among individuals.Previous studies by the group have shown that the pharmacokinetic characteristics of drugs were altered under high altitude hypoxia,but the pharmacokinetics and pharmacodynamics of atorvastatin under high altitude hypoxia have not been reported.This project investigated the effects of high altitude hypoxia on the pharmacokinetics and pharmacodynamics of atorvastatin in hyperlipidemic rats and hyperlipidemic patients through four components.1.Effect of acute and chronic high altitude hypoxia on the pharmacokinetic parameters of atorvastatin in hyperlipidemic rats.The hyperlipidemic wistar rats were randomly divided into normoxia groups（N1,N2）and hypoxia groups（H1,H2）.Group N1 in normoxic environment and group H1 received a 3-day acute hypoxia exposure in a low-pressure oxygen chamber at a simulated altitude of 5500 m,both groups received single gavage administration.Group N2 in normoxic environment and group H2received a 14-day chronic hypoxia exposure in a low-pressure oxygen chamber at a simulated altitude of 5500 m,and both groups received multiple gavage administration for 14 days.Blood samples were collected from the eye socket before（0 h）and 0.083,0.25,0.5,1,1.5,2,2.5,4,6,8,12 and 24 h after the last dose.Blood drug concentrations were determined by LC-MS/MS and pharmacokinetic parameters were obtained.The results indicated that AUC increased by 70.33%,C_max increased by 48.54%and CL decreased by 42.01%in group H1 compared to group N1,indicating increased bioavailability,increased absorption and slowed metabolism of atorvastatin under acute hypoxia.Compared to the N2 group,the AUC and Cmax in the H2 group increased by53.41%and 99.49%,respectively,and MRT and V decreased by 32.84%and 63.18%,respectively,indicating increased bioavailability,increased absorption and reduced vivo residence time of atorvastatin under chronic hypoxia.2.Effect of high altitude hypoxia on the pharmacodynamics of atorvastatin in hyperlipidaemic rats.The effect of hypoxia on the pharmacodynamics of atorvastatin was investigated by measuring the levels of blood lipid,CK and liver transaminases.The results showed that after 7 and 14 d of administration,TG,TC and LDL-C were significantly reduced,HDL-C was significantly increased and CK,liver transaminases were significantly increased under hypoxia conditions,indicating that atorvastatin was more effective in regulating lipids under high altitude hypoxia,but the high plasma drug concentration exposure increased the risk of myotoxicity and hepatotoxicity.3.Population pharmacokinetic of atorvastatin in patients with hyperlipidaemia on the plateau.A nonlinear mixed-effect modelling approach was applied to establish the population pharmacokinetics model of atorvastatin in patients with hyperlipidemia on the plateau and plain.The results showed that area and age had a significant effect on the clearance of atorvastatin,and area,age and urea had a significant effect on the volume of distribution.The clearance of atorvastatin was approximately 1.56 times higher in plain patients than in plateau patients and the distribution volume of atorvastatin was approximately 2.16 times higher in plain patients than in plateau patients.The pharmacokinetic parameters of atorvastatin were differed significantly between plateau and plain hyperlipidaemic patients,with increased bioavailability,increased absorption and slowed metabolism of atorvastatin in the plateau patients.4.Pharmacodynamic evaluation of atorvastatin in patients with hyperlipidaemia on the plateau.The pharmacodynamic differences between atorvastatin in the plateau and plain patients were compared and the results showed that atorvastatin was more effective in reducing TC and LDL-C in plateau patients,clearance and distribution volume of atorvastatin were positively correlated with the rate of change in TC and LDL-C from baseline levels,suggesting that lower clearance and volume of distribution were associated with better efficacy.In summary,high altitude hypoxia altered the pharmacokinetics and pharmacodynamics of atorvastatin.Atorvastatin bioavailability increased and metabolism decreased in high-fat rats under acute hypoxia,while atorvastatin bioavailability increased,absorption increased and residence time in vivo decreased under chronic hypoxia.Atorvastatin was more effective in regulating lipids under hypoxia conditions,but high plasma drug concentration exposure increased the risk of myotoxicity and hepatotoxicity.The clearance and volume of distribution of atorvastatin were significantly lower in plateau patients than plain patients.It is recommended that the dose of atorvastatin should be reduced in the plateau environment,especially in elderly plateau patients,to ensure the safety and efficacy of the drug.