Studies On The Determination Of New Antidepressants In Human Blood And Pharmacokinetics In Rats

Depression is a common mental disease,its main features are low mood,slow thinking,etc.,even suicide behavior.Currently,new antidepressants are the leading drug in clinical for the treatment of depression.However,with the increasing use of new antidepressants,there have been drug abuse and the drug are used in the case of violent crime,in addition,there were some drug combination therapy in clinical,but little research were done on the interaction of drugs combination.In this subject,we study the rapid quantitative methods of new antidepressant drugs,the drug metabolisms of melitracen in rats and the interaction of new antidepressant duloxetine and antipsychotic drugs quetiapine when they used together.Our work can uesd for the forensic identification of antidepressants,and which can provide technical means and reference for drug safety,basic research and clinical research.The details are as follows:1 Ultrasound-assisted low-density solvent dispersive liquid-liquid microextraction（UA-LDS-DLLME）for the simultaneous determination of 12 new antidepressants and 2 antipsychotics in whole blood by GC-MSThe UA-LDS-DLLME was used as sample pretreatment,and established the optimal conditions:100 μL toluene as extractant,add 100 μL pH 12 of ammonia to adjusted pH,ultrasonic 3min.And 14 compound are norfloxetine,fluoxetine,fluvoxamine,agomelatine,mirtazapine,moclobemide,melitracen,desmethyl-mirtazapine,maprotiline,sertraline,citalopram and paroxetine,clozapine and haloperidol.GC/MS was measured as follows:column:DB-5ms（0.25 mm×30 m×0.25 μm）,splitless,injection time 1 min,inlet temperature 280 ℃;oven heating program:100 ℃（1 min）₂0 ℃/min₂00 ℃（5 min）₈ ℃/min₃00 ℃（5 min）.EI source,70 eV;ion source temperature 230 ℃;interface temperature were 300 ℃;solvent delay for 4 min;SIM mode.And norfloxetine-D6 and paroxetine-D6 were as internal standard.The method has specificity,and the compounds had good linear relationship in the range of 15-1500 ng/mL or 5-500 ng/mL,and the accuracy and precision of intra-day（n = 5）and inter-day（n = 15）all meet the requirements（accuracy values were within ± 15%,precision values were below 15%）,most of the compounds’extraction recoveries rate were above 50%.The method had good stability,and was applied in the actual case.2 Metabolism of melitracen in rats based on LC-HRMSBased on the characteristics of high resolution mass spectrometry and the help of analysis software,we bulid the method for the analysis of metabolites of melitracen.The melitracen standard aqueous solution were given to rats by intragastric administration,and the rat urine were collected before administration and at 3,6,9,12,24 hours after administration.The samples were pretreated by solid phase extraction and liquid-liquid extraction.And in the finally,we found melitracen and 30 kinds of it’s I and II metabolites in the rat urine,and we initially inferred the metabolic pathway of melitracen in rats were mainly demethylation and hydroxylation.3 Studies on pharmacokinetics of a combination of duloxetine and quetiapine in ratsA quantitative method for the simultaneous determination of duloxetine and quetiapine in rat plasma was established by LC-MS/MS.A protein precipitation was used for sample preparation.And the plasma endogenous substances and other substances were observed without interference on quetiapine and duloxetine.The method was carried out on an Eclipse XDB-C18 column with an analysis time of 6.0 min.The lower limit of quantification of quetiapine and duloxetine were 0.500 ng/mL and 1.00 ng/mL,respectively.It were good linear in the range of 0.500～100ng/mL for quetiapine and 1.00～200ng/mL for duloxetine,and the overall extraction recovery was 96.7%and 92.6%,respectively.The IS-normalizedmatrix effect is 1.03 for quetiapine and 0.94 for duloxetine,which can meet the requirements of biological samples.This method was successfully applied to the pharmacokinetic study of quetiapine combined with duloxetine.SD rats were randomly divided into 3 groups（n=6）,single administration quetiapine,single administration duloxetine and co-administration of quetiapine and duloxetine,pharmacokinetic parameters were used for evaluated the interaction after dosing.The Cmax and AUC0-∞ of the single group and the combination group for quetiapine were 18.1 ± 14.6 ng/mL,35.2 ± 35.0 h ng/mL and 22.8 ± 15.5 ng/mL,41.2 ±21.1 h ng/mL;the Cmax and AUC0-∞ of the single group and the combination group for duloxetine were 34.4 ± 5.6 ng/mL,372.7 ± 105.9 h ng/mL and 55.9 ± 13.0 ng/mL,544.1 ±56.0 h ng/mL.After the paired t-test,the P value of Cmax and AUC0-∞ between the single group and the combined group for quetiapine were all greater than 0.05,indicating that the combination had no significant effect on the pharmacokinetics of quetiapine.The P value of Cmax and AUC0-∞ between the single group and the combined group for duloxetine were 0.016 and 0.039,respectively,and the P value of AUC0-t was 0.001,indicating that the combination had a significant effect on the pharmacokinetics of duloxetine,and quetiapine can increase the concentration of duloxetine in rats,and its pharmacokinetic parameters Cmax and AUC increased significantly.