| To evaluate the pharmacokinetic properties of inosiplex tablets in healthy Chinese volunteers,LC-MS/MS methods for quantifying inosine,p-acetamino-benzoic acid(PAcBA)and N,N-dimethylamino-2-propanol(DIP)in human plasma were established.The concentration-time curves were drawed and the pharmacokinetic parameters were calculated based on the concentrations determined.The results provided a guidance for clinical medication.A LC-MS/MS method for the determination of inosine and PAcBA in human plasma was developed and validated.The analytes and internal standard felbinac were extracted from plasma with protein precipitation method,then separated on a SUPELCO Ascentis(?)Express C18 column(4.6x150 mm I.D,5 ?m)with gradient elution at a flow rate of 0.8 mL/min.The mobile phase was acetonitrile and water containing ammoniumacetate(5 mmol/L).Mass spectrometric detection was performed on a triple quadrupole tandem mass spectrometer equipped with electrospray ionization(ESI)source in negtive ion mode.Multiple reaction monitoring(MRM)with the transitions of m/z 267.2?m/z 143.9,m/z 178.2?m/z 133.8 and m/z 211.1 ?m/z 166.9 was used for quantification of inosine,PAcBA and IS,respectively.The linear concentration ranges of the calibration curves for inosine and PAcBA were 30-1000 ng/mL and 10-10000 ng/mL,respectively.The lower limit of quantification were 30 ng/mL and 10 ng/mL,respectively.The accuracy,precision,specificity stability,recovery and matrix effects were corresponded to the relevant norm.To develop a LC-MS/MS method for the determination of DIP,a protein precipitation method was employed to pretreat the plasma samples.The analyte and internal standard diazepam were separatd on a SUPELCO Ascentis(?)C18 column(4.6×50 mm I.D.,5 ?m)using a mobile phase consisted of methanol-ammoniumacetate(10 mmol/L)with a gradient elution.The flow rate was 1 mL/min.Detection was performed on a linear ion trap mass spectrometer equipped with electrospray ionization(ESI)source in the positive ion mode.Multiple reaction monitoring(MRM)using ion transitions of m/z 103.9? m/z 71.1,m/z 285.2? m/z 193.1 was employed for quantification of DIP and IS,respectively.The linear concentration range of the calibration curves was 50-3000 ng/mL in human plasma.The lower limit of quantification were 50 ng/mL.The accuracy,precision,specificity stability,recovery and matrix effects were corresponded to the relevant norm.The LC-MS/MS methods were applied to plasma pharmacokinetic studies of inosine,DIP and PAcBA in healthy Chinese volunteers after oral administration of inosiplex tables.The concentration of inosine did not increase obviously with dose enhancement and was maintained in a stable range in healthy volunteers.So the pharmacokinetic parameters calculated here were only for PAcBA and DIP.After a single oral dose of 0.5 g inosiplex tables,AUC0-t for PAcBA and DIP were 3555.10 ± 2469.68 ?g/L h and 4458.32 ± 1299.07 ?g/L·h,respectively.Camx were 3390.50 ± 3949.62 ng/mL and 1080.90 ± 384.93 ng/mL,respectively.T1/2 were 1.15 ± 0.57 h and 3.61 ± 0.93 h,respectively.Tmax were 0.83 ± 0.31 h and 1.18 ± 0.55 h,respectively.After a single oral dose of 1.0 g inosiplex tables,AUC0-t for PAcBA and DIP were 7912.17 ± 4483.07 ?g/L·h and 7656.68 ± 2259.36 ?g/L·h,respectively.Cmax were 7042.00 ± 2610.86 ng/mL and 2081 ± 694.14 ng/mL,respectively.T1/2 were 1.15± 0.42 h and 4.36 ± 1.68 h,respectively.Tmax were 0.63 ± 0.18 h and 0.73 ± 0.18 h,respectively.After a single oral dose of 2.0 g inosiplex tables,AUC0-t for PAcBA and DIP were 18153.28 ± 11416.54 ?g/L·h and 13924.42 ± 2598.47 ?g/L·h,respectively.Cmax were 14838.00 ± 11703.67 ng/mL and 3227.5 ± 964.61 ng/mL,respectively.T1/2 were 1.45 ± 0.69 h and 3.55 ± 0.81 h,respectively.Tmax were 0.95 ± 0.48 h and 1.13 ± 0.48 h,respectively.The effects of high-fat diet on the pharmacokinetic profile:AUC0-t for PAcBA and DIP were 4150.37 ± 2076.22 ?g/L·h and 7243.55 ± 2697.51 ?g/L·h,respectively.Cmax were 1997.10 ± 1459.85 ng/mL and 1497.20 ± 609.23 ng/mL,respectively.T1/2 were 1.23 ± 0.62 h and 3.76 ± 0.80 h,respectively.Tmax were 1.58 ± 0.83 h and 1.90 ± 0.94 h,respectively.After multiple dose administration of inosiplex tables for 7 days,AUC0-t for PAcBA and DIP were 9473.08 ± 3823.29 ?g/L·h and 9791.53 ± 3676.78 ?g/L·h,respectively.Cmax were 9068.89 ± 4349.97 ng/mL and 2415.56 ± 750.51 ng/mL,respectively.T1/2 were 2.09 ± 1.37 h and 3.77 ± 1.62 h,respectively.Tmax were 0.64 ±0.18 h and 0.78 ± 0.38 h,respectively.The statistical results indicated that PAcBA and DIP both had the trend that Cmax,AUC0-t and AUC0-?.linearly related to the dose in this study.Ti/2z,Vz/F and CLz/F,whose P values was more than 0.05,showed no statistically significantly difference within the three doses.The food effect study showed that the high fat food obviously decreased the absorption rate and absorption amount of PAcBA but only slowed down the absorption rate of DIP.Meanwhile,After oral administration at multiple dosage level,the accumulation factor of PAcBA and DIP were 1.24 and 1.12,respectively,which showed that there was no obvious accumulation in human plasma. |
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