Pharmacokinetics Of Repirinast Tablets In Healthy Chinese Volunteers

Objective: To establish a high performance liquid chromatography-tandem mass spectrometric method(LC-MS/MS)for the quantification of metabolite MY-1250 in human plasma,to discusse the effects of pharmacokinetics while concerning multiple dose administration,dose and gender.The aim was to provide a theoretical basis for clinical rational use of drug.Method:(1)To establish a high performance liquid chromatography-tandem mass spectrometric method(LC-MS/MS)for the quantification of metabolite MY-1250 in human plasma.The separation was performed on the Agilent ZORBAX Eclipse plus ?C18(4.6 × 100 mm,3.5 ?m)with the mobile phase consisted of methanol and 6 mmoL·L-1 ammonium acetate containing 0.02% ammonia at a flow rate of 0.8 mL·min-1 under gradient elution.ESI source was applied and operated in multiple reaction monitoring(MRM)mode via positive ionization.Levetiracetam was used as the internal standard and the analysis was detected under the following condition: m/z 286.1?198.2 for MY1250 and m/z 171.3?126.2 for Levetiracetam.Plasma samples were pretreated by methanol precipitation.(2)Pharmacokinetics of repirinast tablets in healthy Chinese volunteers.The trial design was random and open.20 subjects were randomly seperated into 2 groups of group I and group II,Each group of male and female half.Group I was randomly seperated into2 groups of I-1 and I-2.Single dose administration: Three dosage groups of 150 mg,300 mg and 450 mg was taken for the study of single dose administration of pharmacokinetic,I-1 and I-2 groups according to a double cycle cross-over test design,cross taking repirinast tablets 300 mg(2 pieces)and 450 mg(3 pieces)at first day and eighth day respectively,cleaning for a period of 7 days;the subjects of group II take repirinast tablets 150 mg(1 piece)at first day.Before and after the administration,the blood samples were collected.Multiple dose administration: After the subjects of group II completed a single dose administration pharmacokinetics test,started the multiple drug administration of 150 mg dose.Continuous fasting oral administration of 150 mg(1 piece)was taken from the 1st~5th day at every morning and evening,with 250 mL warm water delivery service.The elbow venous blood 3 mL was collected to detective the valley concentration at the 4th~6th day in the morning before medication.The medication and blood sampling of continuous administration at the 6th day was same as single dose administration pharmacokinetics trial.Major Pharmacokinetics parameters were estimated by DAS 3.2.3 and analyzed subsequently with SPSS 17.0.Result:(1)The method was proved to be sensitive,accurate,reproducible and suitable.Endogenous substances do not interfere with the detection of the internal standard and the analyte.A good linearity of metabolite MY-1250 was obtained in the concentration range of 2.000 ~ 1500 ng·mL-1 and the LLOQ was 2.000 ng·mL-1.(2)Pharmacokinetics of repirinast tablets in healthy Chinese volunteers.The effect of dose on pharmacokinetics: In the range of 150~450 mg dose,The AUC0-48h?AUC0-??Cmax were not dose-dependent.There were no statistical differences among the dose range for Tmax,t1/2,MRT0-?,Vd,and CL/F,but there was statistical difference(P<0.05)for MRT0-t.The effect of multiple dose administration on pharmacokinetics: Compared with the single administration,the metabolite MY-1250 in plasma has no accumulation tendency after multiple oral administration of 150 mg repirinast tablets(? = 12 h).The effect of gender on pharmacokinetics: Pharmacokinetics parameters of males and females were statistical analyzed.No significant differences were noted in different group except lnAUC*0-? and CL/F of the high dose group(450 mg).Conclusion:Over the dose range of 150 mg to 450 mg,repirinast isn't characterized by linear pharmacokinetics in healthy volunteers.There was no accumulation following multiple dosing of 150 mg repirinast(?=12 h),and multiple dose administration does not affect its absorption and metabolism speed.Gender only had effect on the pharmacokinetic parameters of the high dose group(450 mg).