| Lobaplatin consists of two diastereoisomers.It belongs to a third-generation platinum antineoplastic agent.Lobaplatin has shown encouraging anticancer activity in several kinds of tumor types.Acquity UPC2 system combines the advantages of supercritical fluid chromatography(SFC)and ultra performance liquid chromatography(UPLC).It uses supercritical fluid as mobile phase.Supercritical fluid has a lot of advantages,chief among them is its low viscosity and high diffusivity.The addition of polar solvent in the mobile phase such as methanol and other polar additives like water,acids and bases gives further polar character to the mobile phase of SFC.As a consequence,SFC has the potential to separate more compounds across wide polarity.Meanwhile,Acquity UPC2 system is based on the technology of UPLC,which makes it has good controllability,precision and sensitivity.In order to investigate any stereospecificity in the pharmacokinetics of lobaplatin in rat,a novel,simple,rapid and sensitive supercritical fluid chromatography-tandem mass spectrometry(SFC-MS/MS)method was developed for the simultaneous quantification of the two diastereoisomers of lobaplatin in rat plasma.After the plasma was precipitated with methanol,the analytes and internal standard(dexpantoprazole)were chromatographed on an Acquity UPC2 system.A Chiralcel OZ-RH column was employed and the mobile phase was carbon dioxide/methanol(65:35,v/v)at 40℃.The analytical time was 6 min.This assay was linear over a concentration range from 25 ng/mL to 15000 ng/mL for the two diastereoisomers and 100 μL of rat plasma was used for sample preparation.The lower limit of quantification(LLOQ)was 25 ng/mL for both diastereoisomers,which was sufficient to detect them in the plasma samples in this study.The intra-and inter-day precisions were below 11.8%and the accuracies were below 4.5%.The method was validated and then was successfully applied to a pharmacokinetic study in rat intravenously injected an administration of 7.6 mg/kg lobaplatin.The pharmacokinetic parameters including AUC0-t,AUC0-∞,Cmax,C0,t1/2,Vd,CL was calculated according to non-compartment model.The AUC0-t,AUC0-∞,t1/2,Vd,CL,Cmax and C0 of LP-D1 are 634 ± 120 μg/mL·min,638 ± 121 μg/mL·min,65.7 士 9.6 min,0.1 ± 0.0 L,1.3 ± 0.6 mL/min,11.6 ± 1.1 pg/mL and 14.6 ± 1.4μg/mL,respectively.The AUC0-t,AUC0-∞,t1/2,Vd,CL,Cmax and C0 of LP-D2 are 576±112μg/mL-min,581± 113 μg/mL·min,74.8± 14.9 min,0.2± 0.1 L,1.3 ±0.6 mL/min,10.7 ± 1.0 μg/mL and 13.3 ± 1.3 μg/mL,respectively.There was no apparent stereospecificity in the pharmacokinetics between the two diastereoisomers of lobaplatin.Additionally,we studied the inhibitory effect of lobaplatin on cytochrome P4501A2,2A6,2B6,3A4,2C9,2C19,2D6 and 2E1.The study employed a probe substance method.Firstly,we incubated the specific substances with human liver microsome.Then the metabolites were quantitated through a LC-MS/MS method.The activity of each P450 subtype was estimated by the concentration of the metabolite.The results showed that lobaplatin didn’t inhibit the activities of cytochrome P4503A4,2C9,2C19,2D6,2E1,2A6 and 2B6 and slightly inhibit 1A2.The inhibition rate was lower than 20%. |
PDF Full Text Request