Preclinical Pharmacokinetic Study Of Dexlansoprazole After Intravenous Infusion

Purpose:In this study,a stereoselective and sensitive column-switching liquid chromatography-tandem mass spectrometry(LC-MS/MS)method was developed and validated for the stereoselective determination of lansoprazole(LAN)enantiomers in beagle dog plasma.The method was successfully applied to a preclinical pharmacokinetic study of dexlansoprazole after intravenous infusion.Method:Plasma samples were analyzed by the established LC-MS/MS method after a simple protein precipitation procedure with cold acetonitrile.The mobile phase was composed of acetonitrile and water with 0.1%formic acid at a flow rate of 1.0 mL/min.A column-switching analytical method was used in the study.Firstly,the analytes were separated by a C18 column from the interference which was not completely eliminated during the sample pretreatment.Then,the fluent was fed to the Chiralcel OZ-RH column for the chiral separation of lansoprazole enantiomers before injected into the LC-MS/MS system.Lastly,mass spectrometry detection was performed on an API 4000 mass spectrometer equipped with an ESI source operated in the positive ionization mode.The ion transition of m/z 370.3?m/z 252.0 was selected for lansoprazole,and the ion transition of m/z 384.1?m/z 200.0 was selected for pantoprazole(PAN)which was used as the internal standard(IS).The linear range of the calibration curves for(+)-LAN and(-)-LAN both ranged from 3.00 to 800 ng/mL.The specificity,linearity,accuracy,precision,the lower limit of quantification,extraction recovery,matrix effect,residual effect and stability were evaluated for method validation according to the relevant guidelines of CFDA.Scheme:Firstly,we investigated the degree of transformation between lansoprazole enantiomers and the consistency of pharmacokinetic properties in beagle dogs after intravenous adminitration of(±)=LAN,(-)-LAN and(+)-LAN.Secondly,we investigated the pharmacokinetic properties in beagle dogs after single intravenous administration of(+)-LAN at three dosage levels and continuous intravenous administration of(+)-LAN at medium dosage for seven days.Rseult:(1)The comparative study of pharmacokinetics between lansoprazole enantiomers.There was no significant difference between the main pharmacokinetic parameters(P>0.05)of(-)-LAN in beagle dogs after intravenous adminitration of(±)-LAN and(-)-LAN,which indicated the pharmacokinetics properties of(-)-LAN had consistencies in beagle dogs after intravenous adminitration of(±)-LAN and(-)-LAN.And there was also no significant difference between the main pharmacokinetic parameters(P>0.O5)of(+)-LAN in beagle dog after intravenous adminitration of(±)LAN and(+)-LAN,and this also indicated the pharmacokinetics properties of(+)-LAN had consistencies in beagle dog after intravenous adminitration of(±)-LAN and(+)-LAN.(2)The pharmacokinetic study of(+)-LAN after intravenous infusion.The main pharmacokinetic parameters after single intravenous administration of(+)-LAN at three dosage levels were calculated with DAS 3.0 software and then analyzed with SPSS 17.0.The result showed that the pharmacokinetics process of(+)-LAN in beagle dog was fitted with linear kinetic model within the dose ranged from 0.2-0.8 mg/kg.After continuous intravenous administration of(+)-LAN at medium dosage for seven days,the accumulation factor of(+)-LAN was 0.77,which indicated that there was no accumulation of(+)-LAN in beagle dog.