| OBJECTIVE: To establish a rapid,sensitive and accurate method for the determination of blonanserin and N-deethylated blonanserin in human plasma by high performance liquid chromatography-tandem mass spectrometry(LC-MS / MS),obtain the pharmacokinetic parameters of Chinese after taking blonanserin that produced by the Li Zhu pharmaceutical factory in the condition of eating high fat,high energy diet and drinking grapefruit.It will provide reference for rational drug use and clinical safety.Methods: This is a open-label,randomized,not multicenter study.Twelve healthy volunteer would participated in the study.Volunteers were fasting overnight at least ten hours.They received 8-mg dose of blonanserin under the following conditions: fasting,30 minutes after eating the meal and drink the grapefruit juice in the meantime on the morning in the first week,the second week and the third week(the drug washout period is seven days).A liquor of blood were taken from upper limb vein before and 0.25,0.5,0.75,1,1,5,2,3,4,6,8,12,24,36,48,60 h after receiving blonanserin,then transferred to calparine tube and centrifuged.The plasma was collected and stored at-20℃for analysis.HPLC-MS/MS methods were used to determine the palsma concentrations of blonanserin.The pharmacokinetic parameters were processed by DSS3.2.4,then evaluated by SPSS13.0.It would evaluate the effect of high fat,high energy diet and grapefruit.Results: Twelve Chinese healthy volunteers were enrolled in this study.All the clinical trials were completed.In this study,the standard curve of the method for determining the concentration of blonanserin and N-deethylated blonanserin in human plasma has good linear ralationship(R2> 0.99),and Lower limit of quantification was consistent with the guiding principle(S/N≥5),the impurity in the plasma does not interfere with the determination of the sample.The matrix effect and the recovery rate are not affected by the determination results.The quantitative lower limit,low,medium and high concentration accuracy and precision meet the requirements.Low and high concentrations of plasma samples were placed at room temperature,multiple freeze-thaw and long-term cryopreservation conditions proved to be stable.The pharmacokinetic parameters of blonanserin were as followed.AUC0-60,fasting was(2588.58±1253.3)ng·h·L-1,AUC0-60,food intake was(6507.33 ±2651.35)ng·h·L-1,AUC0-60,grapefruit was(15215.11±8230.43)ng·h·L-1.AUC0-∞,fasting was(2760.86±1292.49)ng·h·L-1,AUC0-∞,food intke was(6896.61 ±2678.23)ng·h·L-1,AUC0-∞,grapefruit was(17247.59±11631.74)ng·h·L-1.Cmaxfasting was(389.16±161.63)ng·L-1,Cmaxfood intake was(954.99 ±438.59)ng·L-1,Cmaxgrapefruit was(1733.34±766.95)ng·L-1.Tmaxfasting was(1.4±0.86)h,Tmaxfood intake(2.19±0.79)h,Tmaxgrapefruit(1.83±0.72)h.MRT0-60,fasting was(9.22±3.05)h,MRT0-60,food intake was(11.93 ±1.39)h,MRT0-60,grapefruit was(12.82±1.86)h.Vz/Ffasting was(47806.72±16565.02)L,Vz/F food intake was(36807.44 ±20464.69)L,Vz/F grapefruit was(19671.88±12049.47)L;T1/2,fasting was(10.8±5.26)h,T1/2,food intake was(18.30 ±5.53)h,T1/2,grapefruit was(23.53±12.18)h.CLz/Ffasting was(3635.34±1913.77)L·h-1,CLz/F food intake was(1369.65 ±641.65)L·h-1,CLz/F grapefruit was(628.11±370.72)L·h-1.The pharmacokinetic parameters of N-deethylated blonanserin were as followed: AUC0-60,fasting was(3290.80±847.31)ng·h·L-1,AUC0-60,food intake was(3935.51±1338.60)ng·h·L-1,AUC0-60,grapefruit was(5989.55±1434.04)ng·h·L-1.AUC0-∞,fasting was(4165.15± 1293.33)ng·h·L-1,AUC0-∞,food intake was(5262.46±2150.24)ng·h·L-1,AUC0-∞,grapefruit was(8742.70±3314.28)ng·h·L-1.Cmaxfasting was(114.19±27.86)ng·L-1,Cmaxfood intake was(133.38±26.31)ng·L-1,Cmaxgrapefruit was(1044.93±395.39)ng·L-1.Tmaxfasting was(6.83± 1.80)h,Tmaxfood intake was(6.75 ±2.14)h,Tmaxgrapefruit was(6.17 ±1.59)h.MRT0-60,fasting was(22.30±1.85)h,MRT0-60,food intake was(23.60 ±2.31)h,MRT0-60,grapefruit was(24.26 ±1.95)h.Vz/Ffasting was(71190.91±15552.63)L,Vz/Ffood intakewas(62202.55± 25826.07)L,Vz/Fgrapefruit was(45599.91± 8247.55)L.T1/2,fasting was(24.89±6.50)h,T1/2,food intake was(29.30 ±19.17)h,T1/2,grapefruit was(33.77±12.92)h.CLz/Ffasting was(2100.43±690.17)L·h-1,CLz/Ffood intake was(1833.28±909.41)L·h-1,CLz/Fgrapefruit was(1044.93±395.39)L·h-1.The pharmacokinetic parameters AUC0-60,food intake,AUC0-∞,food intake,Cmaxfood intake,Tmaxfood intake of blonanserin were significantly higher than those of fasting(P <0.05).AUC0-60,food intake is 2.51 times higher than AUC0-60,fasting and Cmaxfood intake is 2.45 times higher than Cmaxfasting.The relative quantity of blonanserin that absorped into the blood circulation increased after food intake.The pharmacokinetic parameters T1/2,food intake were significantly longer than those of fasting(P <0.05).The pharmacokinetic parameters Clz/Ffood intake were significantly lower than those of fasting(P <0.05).And there was no statistically significant difference in the pharmacokinetic parameters of N-deethylated blonanserin between these two condition.The pharmacokinetic parameters AUC0-60,grapefruit,AUC0-∞,grapefruit,Cmaxgrapefruit of blonanserin were significantly higher than those of fasting(P <0.05).AUC0-60, grapefruit,Cmaxgrapefruit of blonanserin were significantly higher than those of fasting(P <0.05).AUC0-60,grapefruit of blonanserin is 5.88 times higher than AUC0-60,fasting and Cmaxgrapefruit of blonanserin is 4.45 times higher than Cmaxfasting.AUC0-60,grapefruit of N-deethylated blonanserin is 1.81 times higher than AUC0-60,fasting and Cmaxfood grapefruit of N-deethylated blonanserin is 9.15 times higher than Cmaxfasting.The relative quantity of blonanserin that absorped into the blood circulation increased after drinking grapefruit.MRT0-60,grapefruit was significantly increased When compare to the pharmacokinetic parameters of fasting.Vz/Fgrapefruit was significantly decreased than that of fasting,T1/2,grapefruit was significantly increased than that of fasting.Clz/F grapefruit was significantly decreased than that of fasting.The pharmacokinetic parameters AUC0-60,grapefruit,AUC0-∞,grapefruit,Cmaxgrapefruit of blonanserin were significantly higher than those after eating high fat,high energy diet(P <0.05).AUC0-60,grapefruit is 2.34 times higher than AUC0-60,food intake and Cmax grapefruit is 1.81 times higher than Cmaxfood intake.The pharmacokinetic parameters T1/2,grapefruit were significantly longer than those after eating high fat,high energy diet(P <0.05).The pharmacokinetic parameters Clz/F grapefruit were significantly lower than those after eating high fat,high energy diet(P <0.05).Conclusion: The Systemic exposure levels of taking blonanserin after eating high fat,high energy diet was significantly improved than those in fasting,but high fat and high-energy diet had no influence on the N-deethylated blonanserin.The Systemic exposure levels of blonanserin and N-deethylated blonanserin of taking blonanserin when drink grapefruit juice at the same time was significantly improved than those in fasting.The Systemic exposure levels of blonanserin of taking blonanserin when drink grapefruit juice at the same time was significantly improved than those of fasting. |
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