去氢骆驼蓬碱衍生物DH-004不同途径给药的大鼠体内药动学研究

Pharmacokinetic study of harmine derivative DH-004 in rats by UPLC-MS/MS after different routes of administration

目的:考察去氢骆驼蓬碱衍生物DH-004不同给药途径在大鼠体内的药动学。方法:分别灌胃(ig)给予Wistar大鼠DH-004 50 mg·kg-1和尾静脉注射(iv)DH-004 10 mg·kg-1。UPLC-MS/MS测定大鼠血浆中DH-004的浓度,采用Kinetica 5.0药动学软件计算药动学参数。结果:口服给药主要药动学参数Cmax,AUClast,CL,Vz,MRT和t1/2分别为(142.57±34.64)ng·m L-1,(566.40±164.27)ng·h·m L-1,(90.60±23.52)L·h-1,(297.15±57.33)L,(4.01±0.35)h和(2.51±0.74)h。尾静脉注射给药的主要药动学参数Cmax,AUClast,CL,Vz,MRT和t1/2分别为(1 894.78±453.96)ng·m L-1,(1 629.93±352.34)ng·h·m L-1,(5.03±0.97)L·h-1,(7.26±2.68)L,(0.83±0.17)h和(1.53±0.27)h。DH-004的绝对生物利用度为6.94%。结论:DH-004口服和静脉给药后在大鼠体内消除较快,绝对生物利用度低。该结果为DH-004的成药性评估提供了科学依据,为其结构改造与剂型设计提供了重要参考。

Objective:To study pharmacokinetics of DH-004 in rats following different routes of administration.Methods:Rats received 50 mg·kg-1DH-004 by oral administration and 10 mg·kg-1DH-004 by caudal vein injection.The plasma concentrations of DH-004 were analyzed by UPLC-MS/MS.The pharmacokinetic parameters were calculated using Kinetica 5.0 software.Results:The main pharmacokinetic parameters for oral administration were:Cmax=(142.57±34.64)ng·m L-1,AUClast=(566.40±164.27)ng·h·m L-1,CL=(90.60±23.52)L·h-1,Vz=(297.15±57.33)L,MRT=(4.01±0.35)h,t1/2=(2.51±0.74)h;The results for caudal vein injection were:Cmax=(1 894.78±453.96)ng·m L-1,AUClast(1 629.93±352.34)ng·h·m L-1,CL=(5.03±0.97)L·h-1,Vz=(7.26±2.68)L,MRT=(0.83±0.17)h,t1/2=(1.53±0.27)h.The absolute bioavailability of DH-004 is 6.94%.Conclusion:DH-004 was eliminated quickly and the absolute bioavailability was low in rats after oral and intravenous administration.The results provide a scientific basis for the evaluation of drug formation of DH-004,and provide important references for the structural modification and formulation design of DH-004.