芹菜素对阿霉素在大鼠体内药动学的影响

目的：研究不同剂量芹菜素对阿霉素在大鼠体内药动学过程的影响。方法：实验设单独给药组和联合给药组，其中单独给药组大鼠给予阿霉素注射液4 mg·kg^-1，经快速静脉注射；联合组大鼠经腹腔注射以不同剂量（7.5，15，30 mg·kg^-1）芹菜素预处理5 d后，快速静脉注射阿霉素注射液4 mg·kg^-1。采用HPLC法测定大鼠血浆及胆汁中阿霉素的浓度，经DAS2.0数据处理软件计算药动学参数。结果：阿霉素单独给药及与不同剂量芹菜素联合给药后，均符合二室模型。研究发现与单独给药组比较，中、高剂量芹菜素联用后阿霉素的药动学参数发生明显改变，分布半衰期（t_1/2α）和清除率（CL）显著降低，而药-时曲线下面积（AUC）和平均滞留时间（MRT）显著增加，消除相半衰期（t_1/2β）延长。与单独组相比，联用组经胆汁的累计排泄量降低，且随剂量增加差异具有统计学意义。结论：中、高剂量芹菜素可显著改变阿霉素的体内药动学过程，其原因可能是芹菜素抑制由MRP1和P-gp所介导的药物外排。

Effects of apigenin on in vivo pharmacokinetics of doxorubicin in rats

OBJECTIVE To investigate effects of different apigenin doses on in vivo pharmacokinetics of doxorubicin in rats.METHODS Single dose group and combination group were designed. Rats in single dose group were given adriamycin 4 mg·kg^-1 by rapid intravenous injection, rats in combination group by intraperitoneal injection of different doses (7.5, 15, 30 mg·kg^-1) of apigenin pretreatment for five days, then rapid intravenous injection of adriamycin 4 mg·kg^-1. Plasma and bile concentrations of doxorubicin were analyzed by HPLC, pharmacokinetic software was used to analyze pharmacokinetic parameters.RESULTS After adriamycin was administered at single dose and combined with apigenin at different doses, two compartment model was satisfied. Compared with single dose group, combination with middle and high dose of apigenin showed significant increased AUC, t_1/2β and MRT of adriamycin, significantly reduced CL and t_1/2α. Compared with single dose group, combination group had significantly decreased bile excretion, and the difference was significant as the dose increased.CONCLUSION Pharmacokinetics process in vivo of doxorubicin is significantly altered by middle and high dose of apigenin, probably because of competitively inhibitory effects of apigenin on efflux transport of doxorubicin mediated by P-gp or MRP1.