| ObjectiveTo retrospectively analyze the results of therapeutic drug monitoring?TDM?of hospitalized inpatients on digoxin?DIG?in a hospital,and simultaneously to investigate the effects of milrinone?MR?on the pharmacokinetics of DIG in rats,there by providing some reference for the rational use of DIG in clinical practice.Methods1.Result analysis of the TDM of hospitalized inpatients on digoxinIt was based on a retrospective analysis,according to the inclusion criteria and exclusion criteria,hospitalized inpatients on DIG whose blood DIG concentrations were detected were selected as subjects from January,2015 up to December,2018.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 SPSS 17.0 to evaluate the relationship between the patient's blood DIG concentrations,and his/her age,sex,weight,hepatic function,renal function,cardiac function,and concomitant use of medications.2.Effect of MR on the pharmacokinetics of DIG in rats16 healthy Sprague Dawley rats were randomly divided into DIG group and DIG-MR group and each group consisted of 7 rats.And were administered in a single dose.In DIG-MR group,MR(0.5mg·kg-1)was given to rats via the tail vein followed by the intragastric use of DIG(0.05mg·kg-1).In DIG group,a corresponding volume of saline was injected to rats via the tail vein before DIG(0.05mg·kg-1)was administered intragastrically to rats.Blood samples were collected from the orbital vein plexus into anticoaglant centrifuge tubes at 0.167,0.33,0.5,1,1.5,2,3,4,6,8,12,24 hours post-dose.The tubes with blood samples were shaken lightly and immediately centrifuged for 10 minutes at 8000 r·min-1.Plasma samples were transferred to Ep tubes,and stored at-80?until analysis.HPLC-MS/MS assay was established to determine the concentrations of digoxin in rat plasma.The liquid-liquid extraction method was adopted to pretreat the plasma samples with methyl tert-butyl ether?MTBE?.Isocratic elution was employed with mobile phase of acetonitrile-0.1%formic acid buffer solution containing 10mmoL ammonium acetate?1:1,V/V?at a flow rate of 0.4mL·min-1.And the column temperature was maintained at 40?.The total running time was 3.5 mins for each sample and 10?L was injected into the HPLC-MS/MS system for analysis.Electrospray ionization?ESI?source was used for massive analysis and detection.Furthermore,mass spectrometric analysis was performed in the positive ion mode and a multiple reaction monitoring?MRM?mode was set up.The MRM transition m/z 798.5?651.8 was selected for quantitative analysis of digoxin and m/z 782.7?636.2 for digitoxin?IS?.The concentrations of DIG in rat plasma were determined at different time points and the pharmacokinetic parameters were calculated and statistically treated by DAS 2.0 and SPSS17.0 software.Results1.The results showed that 166 patients were selected according to the inclusion and exclusion criteria,including 82 men?49.40%?and 84 women?50.60%?.Their average plasma DIG concentrations were?0.95±1.04?ng·mL-11 and?1.25±1.04?ng·mL-1and there was a significant difference in blood concentration of DIG between the two groups?P<0.05?.And their age was 1889 years old.But 63.86%of the cases were 60 years old and over,and their average plasma DIG concentration was?1.15±1.11?ng·mL-1.No statistically significant differences were shown between the plasma digoxin concentrations in different age groups.?P>0.05?.In the total patients cases,DIG concentration<0.5ng·mL-1accounted for 29.51%?49/166?,the average plasma concentration result was?0.31±0.12?ng·mL-1;0.52.0 ng·mL-1accounted for 57.83%?96/166?,the average plasma concentration was?1.03±0.42?ng·mL-1;And>2.0 ng·mL-1accounted for 12.65%?21/166?,the average plasma concentration result was?3.24±1.33?ng·mL-1.In 14.46%?24/166?of the patients,adverse DIG reactions appeared of those patients,10 patients showed adverse DIG reactions in the therapeutic DIG range(0.52.0ng·mL-1)and 14 toxic cases of DIG concentration>2.0ng·mL-1and appeared to adverse drug reactions.The symptoms mainly included gastrointestinal reactions,arrhythmia,central nervous system symptoms and so on.Aspartate aminotransferase?AST?and alanine aminotransferase?ALT?had no marked effects on the plasma DIG levels?P>0.05?.Whereas body mass index?BMI?,creatinine clearance rate?Ccr?,cardiac function,significantly affected plasma DIG concentrations?P<0.05?.The administration of DIG and MR,reduced plasma DIG concentrations to?0.78±0.55?ng·mL-1from?1.25±1.15?ng·mL-1?P<0.05?.MR affects the changes of plasma drug concentration in DIG.In addition to the individual differences caused by the physiological and pathological characteristics of patients,MR may also change the hemodynamic characteristics of the body and the pharmacokinetic characteristics of DIG.2.HPLC-MS/MS assay was established to determine the plasma concentrations of DIG,It has high specificity,low matrix effects and good resolution for the determination of plasma DIG and IS.At the same time,endogenous and exogenous substances have no interference in the determination.The result demonstrated that AUC?0-t?were?70.83±69.39?ng·mL-1·h and?58.82±27.24?ng·mL-1·h in DIG group and DIG+MR group respectively.The Tmaxax were?1.28±1.02?h and?0.92±0.20?h,respectively.The Cmaxax were?9.66±3.70?ng·mL-1and?12.50±4.67?ng·mL-1,respectively.And the CL were?0.0010±0.0008?L·h-1·kg-11 and?0.0020±0.0021?L·h-1·kg-1,respectively.Nevertheless,the statistical analysis indicated that there were no significant differences in the pharmacokinetic parameters(AUC,t1/2,Tmax,Cmax,CL,Vd)of DIG between the two groups?P>0.05?.Conclusions1.The factors-influenced digoxin concentrations include sex,age,body mass index?BMI?,renal function,cardiac function,MR-DIG combination,etc.Nevertheless,the liver function had no significant effects on the plasma DIG concentrations.2.The HPLC-MS/MS method was established for the determination of digoxin concentration in rat plasma.This indicated that the method was feasible for the analysis of digoxin.The research found that after the administration of MR and DIG to rats,DIG exposure would be reduced,DIG mean residence time and DIG peaking time were shortened,and DIG absorption degree and DIG absorption were accelerated.Therefore,when the DIG and MR are concomitantly,used the dose of DIG should be appropriately adjusted.To ensure patient safety and prevent adverse DIG effects,plasma DIG concentrations in patients on DIG should be detected.3.Taken together,When clinical pharmacists perform TDM,they not only should pay attention to patients blood drug concentrations,but also should closely cooperate with clinicians and should consider patients physiology,pathology,blood hematology,biochemistry,urinalysis,clinical signs and symptoms,concomitant administration of medications and etc.Moreover,they must carry our comprehensiveiy evaluation of patients and develop individualized dosing regimens promote rational use of medications. |
PDF Full Text Request