Effects Of Diets And High Altitude Environment On The Pharmacokinetic Parameters Of Nifedipine

ObjectiveNifedipine is a widely used drug for the treatment of hypertension in recent years,nevertheless accompanied by more and more reports of side effects.As the pharmacokinetic parameters are affected by a variety of factors.Pharmacokinetic parameters are important theoretical basis for guiding clinical medication,and their changes are closely related to the safety and effectiveness of clinical medication.Therefore,it is of great significance to clarify the factors that affect the pharmacokinetic parameters for improving the rationality of clinical medication.This study clarified the factors affecting the pharmacokinetic parameters of nifedipine and the research status through literature review.Then,the effect of diet?high-fat diet and grapefruit?on the pharmacokinetic parameters of nifedipine was evaluated by Meta analysis.High altitude hypoxia environment is another major factor affecting the pharmacokinetic parameters of nifedipine,but the effect of high altitude environment on human pharmacokinetic parameters has not been reported in literature.This study designed rats to study the effects of high altitude environment on human pharmacokinetic parameters,which lays a theoretical foundation for the development of human pharmacokinetics of nifedipine at high altitude.MethodsMeta-analysis about effects of diets on pharmacokinetic parameters of nifedipine in human bodyThe literatures related to the pharmacokinetic parameters of nifedipine were selected from some databases,such as China How Net,Wanfang Database,Weipu Database,Embase,Pubmed and the Cochrane Library.The retrieval time of literatures was from the establishment of the database to 2018.12.31.The effects of high-fat diet and grapefruit on the pharmacokinetic parameters of nifedipine in human body in a randomized controlled study were collected.Two evaluators screened,included and extracted relevant research data,and evaluated the quality of studies by Cochrane Collaborative Network Bias Risk Tool.Finally,we analyzed and evaluated the extracted data by RevMan 5.3.5 software.The effects of plateau hypoxic environment on pharmacokinetic parameters of nifedipineThe rats were randomly divided into the plain group and the plateau group.After blood collection,UPLC-MS/MS method was used to determine the plasma drug concentration.The pharmacokinetic parameters were calculated using DAS 2.0 software,and Spass13.0 was used for statistical analysis.Changes of metabolism of nifedipine mediated by intestinal flora in a plateau hypoxic environmentThe specific changes of intestinal flora of rats in the plateau hypoxia environment were analyzed by 16S rRNA method,and the amount of nifedipine remaining in the incubation system and the amount of oxidated nifedipine production were analyzed by combining the incubation method and UPLC-MS/MS method.ResultsMeta-analysis about effects of diets on pharmacokinetic parameters of nifedipine in human bodyThe results of Meta-analysis showed that high-fat diet and grapefruit markedly increased T_max?C_max and AUC_0-?pharmacokinetic parameters of nifedipine.The effects of plateau hypoxic environment on pharmacokinetic parameters of nifedipineBy comparing the pharmacokinetic parameters of nifedipine between the plain group and the higher hypoxia environment group,we discovered that the AUC(AUC_0-?and AUC_0-t)and MRT(MRT_0-?and MRT_0-t)of nifedipine in the high altitude group increased by 56.43%,59.78%,24.57%and 42.3%respectively compared with the plain group.However,T_max,CL and V decreased,and CL decreased by 57.15%?P<0.05?,and other changes had no significant difference.Changes of metabolism of nifedipine mediated by intestinal flora in a plateau hypoxic environmentCompared with the plain group,the 16S rRNA results showed that the intestinal flora of rats in the plateau low-oxygen environment was out of balance,and the number of flora presented a downward trend.The incubation results showed that compared with the incubation for 0h,the metabolism of nifedipine was 23.14%in the plain group and 10.84%in the plateau group after 12h of incubation.After incubation for 24h,the metabolites of nifedipine in the plain group and the plateau group were 53.72%and 34.79%,respectively.The results confirmed that the imbalance of intestinal flora in the plateau low-oxygen environment slowed down the metabolism of nifedipine,which was one of the reasons for the changes in the pharmacokinetic parameters of nifedipine.ConclusionHigh-fat diet and grapefruit can increase the bioavailability of nifedipine,and then cause changes in its efficacy.Therefore,it is recommended to avoid high-fat food and grapefruit when taking nifedipine.The pharmacokinetic parameters of nifedipine were significantly affected by the plateau hypoxic environment,which is mainly reflected in increased absorption,decreased clearance rate and increased bioavailability.This is because the intestinal flora disorder in the plateau environment slows down the metabolism of nifedipine,suggesting that the dosage of nifedipine may need to be adjusted in the plateau hypoxia.In conclusion,the above influencing factors are the important factors affecting the changes of pharmacokinetic parameters of nifedipine.Clinicians or pharmacists need to combine the actual situation of patients to propose a reasonable medication time and dose,so as to improve the rationality of clinical medication of nifedipine.