复方甲苯咪唑在鲫体内的药物动力学研究
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摘要
本试验建立了鲫血浆及组织中甲苯咪唑和左旋咪唑的液-液萃取方法、离子对高效液相色谱定量方法。采用pH11.0的碳酸盐缓冲液和乙酸乙酯作为萃取试剂。选用十二烷基硫酸钠(SDS)作为离子对试剂。用Agilent Extend-C18 (250mm×4.6mm, 5μm)色谱柱对血浆及组织样品中的甲苯咪唑和左旋咪唑进行分离,以乙腈-离子对缓冲液(35：65,v/v)作为流动相,流速1.0mL/min,紫外检测波长220nm,柱温40℃作为鲫血浆及组织中甲苯咪唑和左旋咪唑的色谱检测条件。经试验,甲苯咪唑在血浆及各组织中的回收率均在75.08%以上,日内变异系数均小于等于4.83%,日间变异系数均小于等于8.98%。左旋咪唑在血浆及各组织中的回收率均在70.90%以上,日内变异系数均小于等于5.63%,日间变异系数均小于等于10.38%,甲苯咪唑和左旋咪唑的血浆及组织标准工作曲线线性关系好,相关系数均在0.9990以上,甲苯咪唑和左旋咪唑在鲫血浆及组织中的定量限均为0.05μg/mL或0 .05μg/g。
对鲫以15mg/kg-bw的剂量单次口灌复方甲苯咪唑(甲苯咪唑：左旋咪唑=4：1)进行血浆及组织的药物动力学研究。血浆中的药物动力学研究表明,甲苯咪唑和左旋咪唑在血浆中的药时数据均符合一级吸收一室开放模型,药时曲线方程分别为：C=13.39(e-0.07t-e-0.17t)、C=4.42(e-0.09t-e-0.28t)。甲苯咪唑主要的药物动力学参数为：t1/2Ka为4.04h、t1/2β为10.15h、AUC为118.11μg-h/mL、CLb为0.10L/(kg·h)、Vd/F为1.49L/kg、Tmax为8.92h、Cmax为4.39μg/mL;左旋咪唑主要的药物动力学参数为：t1/2Ka为2.50h、t1/2β为7.40h、AUC为31.20μg·h/mL、CLb为0.10L/(kg·h)、Vd/F为1.03L/kg·Tmax为5.91h、Cmax为1.68μg/mL
组织中的药物动力学研究表明,甲苯咪唑和左旋咪唑在各组织中穿透力强,能透过血脑屏障,在肝脏中吸收最快、分布最多,皮肤中消除最慢。除在肝胰脏和肾脏中药时曲线符合二室开放模型外,在其余组织中均符合一室开放模型。甲苯咪唑在肌肉、皮肤、脑、肝胰脏和肾脏中的t1/2Ka依次为4.80、3.11、7.05、2.42、4.53h。t1/2β依次为7.70、23.14、11.95、17.69、12.49h。Tmax依次为8.69、10.40、13.09、5.83、9.84h。Cmax依次为3.44、3.25、2.64、9.70、3.82μg/g。AUC依次为83.58、148.31、97.36、257.06、116.94μg·h/g。药时曲线方程分别为C=19.98(e-0.09t-e-0.14t)、C=5.13(e-0.03t-e-0.22t)、C=13.77(e-0.06t-e-0.10t)、C=22.09e-0.17t+9.24e-0·04t-31.33e-0.29tC=3.97e-0.10t+8.85e-0.06t-12.82e-0.15t。左旋咪唑在肌肉、皮肤、脑、肝胰脏和肾脏中的tl/2Ka依次为2.62、2.53、4.25、2.75、2.57h。t1/β依次为8.61、17.01、9.30、12.76、13.12h。Tmax依次为6.46、8.16、8.85、5.65、6.39h。Cmax依次为1.16、1.31、0.93、3.29、2.57μg/g。AUC依次为24.24、44.67、24.13、68.93、59.76μg·h/g。药时曲线方程分别为C=2.81(e-0.08t-e-0.26t)、C=2.14(e-0.04t-e-0.27t)、C=3.31(e-0.07t-e-0.16t)、C=13.53e-0.17t+2.98e-0.05t-16.51e-0.25t、C=3.84e-0.12t+2.82e-0.05st-6.66e-0.27t。
In this research, A liquid-liquid extraction method was established for the extraction of both mebendazole and levamisole in crucian carp's plasma and tissues with pH11.0 icarbonate buffer and ethyl acetate as the extration reagents.MBZ and LMS concentrations in plasma and tissues were quantitated by means of ion-pair high-performance liquid chromatography (HPLC).Ion-pair reagent was achieved with SDS.Separation was achieved with an Agilent Extend-C18 (250mm×4.6mm,5μm) colunm. A mixture of acetonitrile-ion pair buffer (35:65,v/v) was used as the mobile phase at a flow rate of 1mL/min. Colunm temperature was maintained at 40℃and the UV detection wavelength was set at 220nm. The recovery of MBZ in plasma and tissues was higher than 75.08%, the intra-day and inter-day coefficients of variation were less than 4.83% and 8.98%, respectively. The recovery of LMS in plasma and tissues was higher than 70.90%, the intra-day and inter-day coefficients of LMS were less than 5.63% and 10.38%,respectively. For both MBZ and LMS the correlation of calibration curve were all good, which correlation coefficient were all more than 0.9990.The limit of quantification (LOQ) for both MBZ and LMS were all 0.05μg/mL or 0.05μg/g in plasma and tissues.
Carassius auratus were administered orally with a single dosage of 15mg/kg body weight of compound mebendazole (mebendazole:levamisole=4:1)in the pharmacokinetics group.The result showed that the plasma concentration-time data of MBZ and LMS conformed to one-compartment open model with 1st order absorption, the curve of concentration-time were C=13.39(e-0.07t-e-0.17t) and C=4.42(e-0.09t-e-0.28t), respectively. The absorption half-life (t1/2Ka) of MBZ was 4.04h, the elimination half-life (t1/2p) was 10.15h, the area under the serum concentration-time curve (AUC)was 118.11μg·h/mL.The total clearance (CLb) was estimated to be 0.10L/(kg·h).The time-point of maximum plasma concentration of the drug (Tmax) and the maximum plasma concentration (Cmax) were calculated as 8.92h and 4.39μg/mL, The t1/2Ka of LMS was 2.50h, t1/2βwas 7.40h, AUC was 31.20μg·h/mL, CLb was estimated to be 0.10L/(kg·h),Tmax and Cmax were calculated as 5.91h and 1.68μg/mL.
The pharmacokinetics of tissues revealed that MBZ and LMS penetrating the organizations easily, such as blood-brain barrier, the fastest absorption is in liver, the slowest elimination is in skin. With the exception of liver and kidney medicine at the curve in the two-compartment open model, the remaining tissues were in the one-compartment open model.The absorption half-life of MBZ in muscle, skin, brain, liver and kidney were 4.80,3.11,7.05,2.42,4.53h. The elimination half-life were 7.70, 23.14,11.95,17.69,12.49h. The peak time were 8.69,10.40,13.09,5.83,9.84h. The peak concentration were 3.44,3.25,2.64,9.70,3.82μg/g. The area under concentration-time curve were 83.58,148.31,97.36,257.06,116.94μg·h/g. The curve of concentration-time were C=12.26(e-0.09t-e-0.14t),C=5.13(e-0.03t-e-0.22t),C=40.34(e-0.06t-e-0.10t), C=22.09e-0.17t+9.24e-0.04t-31.33e-0.29, C=3.97e-0.10t+8.85e-0.06t-12.82e-0.15t,The absorption half-life of LMS in muscle, skin, brain, liver and kidney were 2.62,2.53,4.25,2.75,2.57h. The elimination half-life were 8.61,17.01,9.30,12.76,13.12h.The peak time were 6.46, 8.16,8.85,5.65,6.39h. The peak concentration were 1.16,1.31,0.93,3.29,2.57μg/g.The area under concentration-time curve were 24.24,44.67,24.13,68.93,59.76μg·h/g.The curve of concentration-time were C=2.81(e-0.08t-e-0.26t),C=2.14(e-0.04t-e-0.27t), C=3.31(e-0.07t-e-0.16t), C=13.53e-0.17t+2.98e-0.05t-16.51e-0.25t,C=3.84e-0.12t +2.82e-0.05t-6.66e-0.27t.
对鲫以15mg/kg-bw的剂量单次口灌复方甲苯咪唑(甲苯咪唑：左旋咪唑=4：1)进行血浆及组织的药物动力学研究。血浆中的药物动力学研究表明,甲苯咪唑和左旋咪唑在血浆中的药时数据均符合一级吸收一室开放模型,药时曲线方程分别为：C=13.39(e-0.07t-e-0.17t)、C=4.42(e-0.09t-e-0.28t)。甲苯咪唑主要的药物动力学参数为：t1/2Ka为4.04h、t1/2β为10.15h、AUC为118.11μg-h/mL、CLb为0.10L/(kg·h)、Vd/F为1.49L/kg、Tmax为8.92h、Cmax为4.39μg/mL;左旋咪唑主要的药物动力学参数为：t1/2Ka为2.50h、t1/2β为7.40h、AUC为31.20μg·h/mL、CLb为0.10L/(kg·h)、Vd/F为1.03L/kg·Tmax为5.91h、Cmax为1.68μg/mL
组织中的药物动力学研究表明,甲苯咪唑和左旋咪唑在各组织中穿透力强,能透过血脑屏障,在肝脏中吸收最快、分布最多,皮肤中消除最慢。除在肝胰脏和肾脏中药时曲线符合二室开放模型外,在其余组织中均符合一室开放模型。甲苯咪唑在肌肉、皮肤、脑、肝胰脏和肾脏中的t1/2Ka依次为4.80、3.11、7.05、2.42、4.53h。t1/2β依次为7.70、23.14、11.95、17.69、12.49h。Tmax依次为8.69、10.40、13.09、5.83、9.84h。Cmax依次为3.44、3.25、2.64、9.70、3.82μg/g。AUC依次为83.58、148.31、97.36、257.06、116.94μg·h/g。药时曲线方程分别为C=19.98(e-0.09t-e-0.14t)、C=5.13(e-0.03t-e-0.22t)、C=13.77(e-0.06t-e-0.10t)、C=22.09e-0.17t+9.24e-0·04t-31.33e-0.29tC=3.97e-0.10t+8.85e-0.06t-12.82e-0.15t。左旋咪唑在肌肉、皮肤、脑、肝胰脏和肾脏中的tl/2Ka依次为2.62、2.53、4.25、2.75、2.57h。t1/β依次为8.61、17.01、9.30、12.76、13.12h。Tmax依次为6.46、8.16、8.85、5.65、6.39h。Cmax依次为1.16、1.31、0.93、3.29、2.57μg/g。AUC依次为24.24、44.67、24.13、68.93、59.76μg·h/g。药时曲线方程分别为C=2.81(e-0.08t-e-0.26t)、C=2.14(e-0.04t-e-0.27t)、C=3.31(e-0.07t-e-0.16t)、C=13.53e-0.17t+2.98e-0.05t-16.51e-0.25t、C=3.84e-0.12t+2.82e-0.05st-6.66e-0.27t。
In this research, A liquid-liquid extraction method was established for the extraction of both mebendazole and levamisole in crucian carp's plasma and tissues with pH11.0 icarbonate buffer and ethyl acetate as the extration reagents.MBZ and LMS concentrations in plasma and tissues were quantitated by means of ion-pair high-performance liquid chromatography (HPLC).Ion-pair reagent was achieved with SDS.Separation was achieved with an Agilent Extend-C18 (250mm×4.6mm,5μm) colunm. A mixture of acetonitrile-ion pair buffer (35:65,v/v) was used as the mobile phase at a flow rate of 1mL/min. Colunm temperature was maintained at 40℃and the UV detection wavelength was set at 220nm. The recovery of MBZ in plasma and tissues was higher than 75.08%, the intra-day and inter-day coefficients of variation were less than 4.83% and 8.98%, respectively. The recovery of LMS in plasma and tissues was higher than 70.90%, the intra-day and inter-day coefficients of LMS were less than 5.63% and 10.38%,respectively. For both MBZ and LMS the correlation of calibration curve were all good, which correlation coefficient were all more than 0.9990.The limit of quantification (LOQ) for both MBZ and LMS were all 0.05μg/mL or 0.05μg/g in plasma and tissues.
Carassius auratus were administered orally with a single dosage of 15mg/kg body weight of compound mebendazole (mebendazole:levamisole=4:1)in the pharmacokinetics group.The result showed that the plasma concentration-time data of MBZ and LMS conformed to one-compartment open model with 1st order absorption, the curve of concentration-time were C=13.39(e-0.07t-e-0.17t) and C=4.42(e-0.09t-e-0.28t), respectively. The absorption half-life (t1/2Ka) of MBZ was 4.04h, the elimination half-life (t1/2p) was 10.15h, the area under the serum concentration-time curve (AUC)was 118.11μg·h/mL.The total clearance (CLb) was estimated to be 0.10L/(kg·h).The time-point of maximum plasma concentration of the drug (Tmax) and the maximum plasma concentration (Cmax) were calculated as 8.92h and 4.39μg/mL, The t1/2Ka of LMS was 2.50h, t1/2βwas 7.40h, AUC was 31.20μg·h/mL, CLb was estimated to be 0.10L/(kg·h),Tmax and Cmax were calculated as 5.91h and 1.68μg/mL.
The pharmacokinetics of tissues revealed that MBZ and LMS penetrating the organizations easily, such as blood-brain barrier, the fastest absorption is in liver, the slowest elimination is in skin. With the exception of liver and kidney medicine at the curve in the two-compartment open model, the remaining tissues were in the one-compartment open model.The absorption half-life of MBZ in muscle, skin, brain, liver and kidney were 4.80,3.11,7.05,2.42,4.53h. The elimination half-life were 7.70, 23.14,11.95,17.69,12.49h. The peak time were 8.69,10.40,13.09,5.83,9.84h. The peak concentration were 3.44,3.25,2.64,9.70,3.82μg/g. The area under concentration-time curve were 83.58,148.31,97.36,257.06,116.94μg·h/g. The curve of concentration-time were C=12.26(e-0.09t-e-0.14t),C=5.13(e-0.03t-e-0.22t),C=40.34(e-0.06t-e-0.10t), C=22.09e-0.17t+9.24e-0.04t-31.33e-0.29, C=3.97e-0.10t+8.85e-0.06t-12.82e-0.15t,The absorption half-life of LMS in muscle, skin, brain, liver and kidney were 2.62,2.53,4.25,2.75,2.57h. The elimination half-life were 8.61,17.01,9.30,12.76,13.12h.The peak time were 6.46, 8.16,8.85,5.65,6.39h. The peak concentration were 1.16,1.31,0.93,3.29,2.57μg/g.The area under concentration-time curve were 24.24,44.67,24.13,68.93,59.76μg·h/g.The curve of concentration-time were C=2.81(e-0.08t-e-0.26t),C=2.14(e-0.04t-e-0.27t), C=3.31(e-0.07t-e-0.16t), C=13.53e-0.17t+2.98e-0.05t-16.51e-0.25t,C=3.84e-0.12t +2.82e-0.05t-6.66e-0.27t.
引文
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