TDM Analysis Of Nifedipine In A Hospital And The Effect Of Glycyrrhizic Acid On The Pharmacokinetics Of Nifedipine In Rats And Human Body

Objective:To retrospectively analyze the results of therapeutic drug monitoring?TDM?of hospitalized inpatients on nifedipine in a hospital,and simultaneously to investigate the effects of glycyrrhizic acid on the pharmacokinetics of nifedipine in rats and human body,there by providing some reference for the rational use of nifedipine in clinical practice.Methods:?1?It was based on a retrospective analysis,hospitalized inpatients on nifedipine whose blood nifedipine concentrations were detected were selected as subjects from January 2019 to June 2019.The following data and findings were collected in patients'medical record and clinical information,such as patient's general condition,the basic condition of the disease,biochemical results,and combined drug use and etc.The abovementioned data and findings were pooled.Thereafter,the pooled facts were statistically analyzed using Excel 2007 and Sp SS 17.0 to evaluate the relationship between the patient's blood nifedipine concentrations,and his/her age,sex,weight,hepatic function,renal function and concomitant use of medications.?2?Rats were randomly divided into experimental group and control group,The experimental group and the control group were given glycyrrhizic acid 5 mg·kg^-1and placebo from the second day,With 14 days of treatment,respectively.on the 2nd day?single administration?and the 15th day?multiple administration?,both groups were given nifedipine 3 mg·kg^-1intragastrically.Blood samples 0.3m L were collected from intraocular vein plexus before and at 0.25,0.5,0.75,1,1.5,2,3,4,6,8,12 and24h after intragastric administration.The concentration of nifedipine was determined by Hp LC using diazepam as internal standard.The determination was performed on ODS-C18 column with mobile phase consisted of methanol-water?62:38,V/V,p H adjusted to 4.5 with acetic acid?at the flow rate of 1.0 m L·min.The column temperature was 30?.The detection wavelength was set at 238 nm,and sample size was 20?L.The pharmacokinetic parameters were calculated with Winonlin 6.0 software,and statistical analysis was performed by t-test.At the end of blood collection,euthanasia was carried out immediately.The liver of rats was collected and the protein content of CYP3A4 was detected by western blot.?3?16 subjects were randomly divided into the experimental group and the control group,the experimental group and the control group were given nifedipine controlled release tablets?30mg qd po?+diammonium glycyrrhizinate capsules?150mg tid po?and nifedipine controlled release tablets?30mg qd po?+placebo,With 14 days of treatment,respectively.In both groups,5ml of fasting blood was drawn in the morning on the 2nd day?single administration?and the 15th day?multiple administration?,and the concentration of nifedipine was determined by Hp LC.Results:?1?Among the 249 patients,157 were male and 92 were female.Their average plasma nifedipine concentrations were?18.37±9.2?ng·m L^-1and?16.68±7.5?ng·m L^-1and there was a significant difference in blood concentration of nifedipine between the two groups?P<0.05?.Among the 249 patients,the age range was 19-93 years old and the mean age was?59.35±13.68?years old.According to the age,they are divided into four groups:19 to 40 years old group,41 to 60 years old group,61 to 80 years old group,and>80 years old group..The results showed that with the increase of age,the serum concentration of nifedipine was higher and higher.There were significant differences between<60 years old group and 19?40 years old group?P<0.05?;according to the body mass index,249 patients were divided into four groups:obese,overweight,normal and low weight.With the decrease of body mass index?BMI?,the average plasma concentration of nifedipine was gradually increased.There were significant differences between the obesity group and the normal weight group and the underweight group and the overweight group?P<0.05?.There was statistical difference between the underweight group and the normal weight group and the overweight group?P<0.05?.249 patients were divided into two groups:the normal liver function group and the abnormal liver function group.With the increase of AST,the average blood concentration of patients increased gradually,from?17.89±8.2?ng·ml^-1in the normal group to?21.87±5.6?ng·ml^-1,with a statistically significant difference?P<0.05?;with the increase of alt,the average blood concentration of patients increased gradually,from?17.37±8.2?ng·ml^-1in the normal group to?20.68±5.9?ng·ml^-1,with a statistically significant difference?P<0.05?;249 patients were divided into 5 groups according to GFR.With the decrease of renal function,the blood concentration of nifedipine did not change significantly,and there was no statistical significance between the groups?p>0.05?;249 patients were divided into two groups:Glycyrrhiza group and other groups.The results showed that compared with other drugs,Glycyrrhiza group had no significant difference The mean blood concentration was?16.25±8.91?ng·ml^-1,while the mean blood concentration of other combined groups was?19.48±5.64?ng·ml^-1,the difference was statistically significant?P<0.05?.?2?The main pharmacokinetic parameters of the experimental group and the control group were as follows as t_maxwas?1.40±0.15?,?1.50±0.01?h;c_maxwas?0.15±0.03?,?0.29±0.09?mg·L^-1;t_1/2was?4.70±1.17?,?5.20±1.38?h;AUC_{0-24 h}were?1.00±0.10?,?1.89±0.37?mg·h·L^-1;AUC_0-?was?1.00±0.16?,?1.98±0.32?mg·h·L^-1;MRT was?6.76±0.64?,?6.60±1.36?h,respectively.Compared with control group,c_max,AUC_{0-24 h}and AUC_0-?of nifedipine were decreased significantly in experimental group,with statistical significance?P<0.05?.Compared with nifedipine group,the level of CYP3A4 protein expression in the glycyrrhizic acid group increased significantly?P<0.05?.?3?After single administration,the blood concentration of nifedipine in the experimental group was?24.82±5.07?ng·m L^-1,which was not statistically significant compared with that in the control group?25.59±6.22?ng·m L^-1,?P>0.05?.After multiple administration,the blood concentration of nifedipine in the experimental group was?28.95±4.20?ng·m L^-1,which was statistically significant compared with that in the control group?35.50±5.03?ng·m L^-1?p<0.05?.Conclution:?1?The factors-influenced nifedipine concentrations include sex,age,BMI,liver function,glycyrrhizic acid,etc.Nevertheless,renal function had no significant effects on the plasma nifedipine concentrations.?2?Glycyrrhizic acid can reduce the bioavailability of nifedipine in rats.?3?Continuous administration of glycyrrhizic acid can reduce the blood concentration of nifedipine in human body.