摘要
目的建立HPLC测定大鼠血浆中伊马替尼及其代谢产物GCP74588的浓度,并研究不同浓度复方苦参素注射液对伊马替尼及其代谢产物的药动学的影响。方法将SD大鼠按体质量均衡原则分成复方苦参注射液低、中、高剂量[0.1,0.2,0.4 m L·(100 g)^(-1),i.p.]组和正常对照组,每组6只,复方苦参注射液连续给药9 d,第10天给予30 mg·kg^(-1)甲磺酸伊马替尼灌胃,按时间点采集血样处理并检测。结果低剂量诱导对伊马替尼及CGP74588均无明显影响;中剂量诱导使伊马替尼的C_(max)降低39.68%、CLz/F增加了62.96%、AUC(0-∞)减少35.70%,而对其代谢产物CGP74588无明显影响;高剂量诱导使伊马替尼C_(max)降低49.04%、Vz/F增加了1.04倍,CLz/F增加了48.15%、AUC(0-t)减少了33.23%、AUC_(0-∞)减少了28.96%,MRT(0-∞)增加了47.31%,而其代谢产物CGP74588的C_(max)降低45.15%,CLz/F增加75.29%,AUC(0-∞)降低33.95%、MRT_(0-t)增加18.53%。结论苦参诱导肝脏CYP3A与P-gp使伊马替尼血浆中浓度降低,有可能会导致治疗失败,所以临床医师在使用时应尽量避免合用这2种药物,或者在监测伊马替尼的浓度下使用。
OBJECTIVE To develop an HPLC method for the determination of imatinib and its metabolites CGP74588, and study the induction effects of Fufang Kushen injection on pharmacokinetics of imatinib and CGP74588 in rats. METHODS Twenty-four SD rats were randomly designated as vehicle control, low-dose, medium-dose and high-dose [0.1, 0.2, 0.4 m L·（100 g）-1, i.p.] Fufang Kushen injection treatment groups. The treatment were given once a day for 9 consecutive days. On the experimental day（day 10）, rats were treated with the imatinib（30 mg·kg-1） orally. RESULTS Low-dose Fufang Kushen injection does not influence the pharmacokinetics of imatinib and GCP74588. However, the effects of the medium-and high-dose Fufang Kushen injection on imatinib were significant. In medium-dose group, the C_（max） and AUC（0-∞） of imatinib reduced 39.68% and 35.70%, while the CLz/F increased 62.96%, but it had no obvious effect on its metabolites CGP74588. In high-dose group, imatinib C_（max） and AUC（0-t） were decreased by 49.04% and 33.23%, while Vz/F, CLz/F and MRT（0-∞） were increased by 1.04 times, 48.15% and 47.31%, respectively. Meanwhile, its metabolites CGP74588 C_（max） and AUC（0-∞） reduced 45.15% and 33.95%, with 75.29% and 18.53% increase in CLz/F and MRT（0-t）. CONCLUSION The induction of medium-dose and high-dose Fufang Kushen injection may be related to the induction sites of CYP3A4 and P-gp. In clinical, when imatinib was co-administrated with Fufang Kushen injection, dose adjustment of imatinib should be taken into account.
作者
林高通
徐涛
罗俊
王戟峰
王晨明
莫菊彩
胡国新
LIN Gaotong XU Tao LUO Jun WANG Jifeng WANG Chenming MO Jucai HU Guoxin(Taizhou Cancer Hospita Ningbo First Hospital,Taizhou Maternal and Child Health Hospital,Wenzhou Medical Universit)
出处
《中国现代应用药学》
CAS
CSCD
2016年第12期1547-1552,共6页
Chinese Journal of Modern Applied Pharmacy
基金
温岭市科技计划项目(2013C31115)
