^(125)I-相思子毒素P_2在小鼠体内的血药浓度及其生物利用度

Plasma concentration and bioavailability of ^(125)I-abrin P_2 in mice

目的研究相思子毒素P2(abrinP2)在小鼠体内的血药浓度和生物利用度,为发展相思子毒素新型抗癌药打下基础。方法 ICR小鼠静脉(2.1μg.kg-1)和灌胃(87.5、43.8和21.9μg.kg-1)给予125I-相思子毒素P2(125I-abrinP2)。给药后不同时间内取血,分离血浆,用同位素示踪法检测血浆中的放射性;然后采用三氯乙酸(TCA)沉淀法检测沉淀中的放射性,PKS软件分析房室模型和计算各种参数,并根据灌胃和静脉给药的药-时曲线下面积(AUC0～∞)之比计算绝对生物利用度。结果相思子毒素P2在0.01～50μg.L-1浓度范围内线性关系良好,样品在血浆中的回收率大于85%,日内变异系数(RSD)小于5%。小鼠单次静脉注射2.1μg.kg-1相思子毒素P2的药代动力学参数分别为吸收半衰期(T12Ka)0.46h、消除半衰期(T21Ke)8.63h、药-时曲线下面积(AUC0～∞)为16.84μg.h.L-1;小鼠单次灌胃给予剂量分别为21.9、43.8、87.5μg.kg-1的125I-abrinP2后,吸收半衰期分别为1.26、1.15、0.55h;消除半衰期分别为46.21、46.21、46.19h,AUC0～∞分别为41.42、67.17、119.27μg.h.L-1。结论相思子毒素P2的血药浓度数据拟合为二室模型,在低、中给药剂量范围内符合线性动力学规律。低、中、高剂量灌胃给药的绝对生物利用度分别为24.6%、19.5%、16.7%。

Aim To study the plasma concentration and bioavailability of the abrin P2 in mice, as the basis for developing new anti-cancer drug. Methods ^125 I- abrin P2 was injected intravenously 2. 1 μg·kg^-1 or administered orally 21.9,43.8 and 87.5 μg·kg^-1 , respectively. Blood samples were collected at different time points following drug administration, and the plasma was separated from blood samples. Radioisotopic tracing method combined with trichloroacetic acid （TCA） precipitation was used to determine plasma concentration of ^125I-abrin P2 in mice. The pharmacokinetic parameters were calculated using PKS software, and bioavailability was assessed according to the ratio of the area under concentration-time curve （AUC0-∞ ）. Results The method showed good linear relationship within the concentration range of 0. 01 -50 μg· L^-1, the recovery of abrin P2 from the mouse plasma was over 85% , and the intra-day precision expressed as the relative standard deviation was less than 5%. The T1/2xa, T1/2Ke and AUC0-∞ for intravenously administered abrin P2（2.1 μg · kg^-1） were 0.46 h, 8.63 h,16.84 μg· h · L^-1 respectively;The T1/2Ka T1/2xe and AUC0-∞ for orally administered abrin P2 （87.5,43.8, 21.9 μg · kg^-1） were 1.26,1.15,0.55 h;46.21,46.21,46. 19 h;41.42, 67.17, 119.27 μg · h· L^-1, respectively. Conclusion The plasma concentration-time curves of abrin P2 in mice conformed to two-compartment open model, and in the range of low and middle doses good linear relationship was detected, the bioavailabilities of abrin P2 in mice were 24.6% ,19. 5% ,16.7% , respectively.