Pharmacokinetic Evaluation Of Aripiprazole Long-Acting Preparations In Dogs

Aripiprazole（APZ）is mainly used for the treatment of schizophrenia,compared with other antipsychotics,side effects are small,positive and negative symptoms of mental illness,and the side effects is low,aripiprazole long-acting preparations can be administered once a month,can well improve the medicine-taking compliance with medication,but there is no aripiprazole long-acting preparation on the market in China,aripiprazole long-acting preparations have broad application prospects and value.Therefore,Therefore,it is necessary to evaluate the pharmacokinetics of aripiprazole long-acting preparations in dogs.In this study,an ultra-high performance liquid chromatography tandem mass spectrometry（UPLC-MS/MS）method was established to simultaneously detect the concentration of APZ and dehydroaripiprazole（H-APZ）in plasma,and the method was methodologically verified.The company’s self-made aripiprazole long-acting preparation was tested in vitro pharmacokinetics in dogs,and samples were tested,relevant pharmacokinetic parameters were obtained,and pharmacokinetic evaluation was carried out,and the main research content of the paper was as follows:Part I:APZ-d⁸ was selected as the internal standard for this experiment.Multiple reaction monitoring mode（MRM）using AB SCIEX 6500 mass spectrometry with positive ion mode for spray voltage.Separation was performed using the Waters Acquity UPLC Peptide BEH C18（1.7μm,2.1×50 mm）column,with 0.1%formic acid in water and 0.1%formic acid in acetonitrile as mobile phase,and gradient elution was used for sample separation.Ethyl acetate was selected as an extractant for pretreatment of dog plasma samples,which had a high recovery rate.Part II:Verification of accuracy,precision,selectivity,stability,matrix effects,extraction recovery,sample carryover,etc.The linear range of APZ and H-APZ is 0.05ng/m L-50.0 ng/m L,and the linear fit（R²）of the standard curve>0.9950.Both the accuracy and precision of the APZ and H-APZ are in the±15%range.The extraction recoveries of APZ and H-APZ were 88.54%-96.83%and 85.38%-93.25%,respectively,with no obvious matrix effect.The stability of APZ and its metabolite H-APZ under different conditions was verified,and the results showed that the analyte was stable under the assay conditions.Part III:Pharmacokinetic experiments of aripiprazole long-acting preparation in dogs at a dose of 10.67 mg/kg by intramuscular injection.Plasma concentration detection of pharmacokinetic samples using the established UPLC-MS/MS method.The relevant pharmacokinetic parameters were calculated,and the results showed that the peak concentration(C_max)of APZ and H-APZ was 102.30±3.82 ng/m L and 11.30±1.56 ng/m L,respectively,the peak time(T_max)was 18.00±8.49 h and 72.00±32.94 h,and the area under the drug time curve(AUC_0-t)was 32693.55±629.01 ng·h/m L and 3809.04±639.66 ng·h/m L,respectively.The UPLC-MS/MS method established in this study has high sensitivity,lower limit of quantification of 0.05 ng/m L,and good reproducibility,and the method is applied to the detection of pharmacokinetic samples in dogs,and the relevant pharmacokinetic parameters are obtained,which provides reliable reference value for the preclinical research of a company’s self-made aripiprazole long-acting preparation.