2,3-吲哚醌在大鼠体内的药代动力学研究

Pharmacokinetics of 2,3-indolinedione in rats

目的考察单次静脉注射和口服给予大鼠2,3-吲哚醌后的药代动力学,为该药的新药开发提供依据。方法大鼠给药后经眼眶静脉采大约0.25ml血液,采集时间点为:给予受试物前(0hr)和给予受试物后5、15、30min、1、2、4、6、8h和24h。血液样本采集后置于冰上,并立即取出50μl全血采用甲醇蛋白沉淀进行预处理,奎硫平作为内标。预处理后样品采用LC/MS/MS法进行测定,并用药动学处理软件WinNonlin5.2采用非房室模型计算相关药代动力学参数。结果 SpragueDawley大鼠静脉注射和口服两种制剂的药动学参数(平均值±标准偏差)如下。静脉注射:Tmax为(0.83±0.29)hr,Cmax为(141.53±10.99)μg/L,t1/2为(1.68±0.84)hr,AUC0-t为(1068.15±389.06)μg/hr/L,AUC0-∞为(1211.19±469.18)μg·hr/L,Vz为(4.13±1.41)L/kg,CLz为(1.89±0.94)L/hr/kg;口服:Tmax为(0.05±0.00)hr,Cmax为(1725.53±469.70)ng/ml,t1/2为(4.21±2.78)hr,AUC0-t为(7711.21±2533.12)μg/hr/L,AUC0-∞为(7986.07±2623.38)μg/hr/L,以AUC0-t计算,生物利用度平均为(57.75±18.97)%。结论 2,3-吲哚醌大鼠体内消除较快,可能存在非线性消除,口服吸收较好。

Objective To study the pharmacokinetics of 2,3-indolinedione in rats after single administration of the drug orally or intravenously and to provide some information for the development of the new drug. Methods 0.25 ml blood were sampled from rats before and 5,15,30 min,1,2,4,6,8, 24 h after drug administration.The blood samples were pretreated by protein precipitation method using methanol. Quetiapine was used as internal standard. After pretreatment, the samples were assayed by LC/MS/MS mothod and the pharmacokinetic parameters were calculated by WinNonlin 5.2 using non-compartment model. Results The pharmaceutical parameters in rats after single administration of the drug orally or intravenously（average±SD）were as follow. Iv：TmaxCmaxt1/2 AUC0-t AUC0-∞Vz and CLz were （0.83±0.29）hr,（141.53±10.99）μg/L, （1.68±0.84）hr,（1068.15±389.06）μg/hr/L, （1211.19±469.18）μg/hr/L,（4.13±1.41）L/kg,（1.89±0.94）L/hr/kg;oral：TmaxCmaxt1/2 AUC0-t AUC0-∞Vz and cLz were （0.05±0.00）hr,（1725.53±469.70）ng/ml,（4.21±2.78）hr,（7711.21±2533.12）μg/hr/L,（7986.07±2623.38）μg/hr/L, the bioavailability（AUC0-t）was （57.75±18.97）%.Conclusion 2,3-indolinedione in rats after single administration of the drug orally has rapid elimination and good absorption.