摘要
目的 分析伊马替尼、瑞戈非尼与华法林的体内药动学相互作用,评估相互作用对华法林药动学的影响。方法 将18只SD大鼠随机分为3组(n=6):A组予生理盐水(10 mL·kg^(-1))+华法林(2 mg·kg^(-1)),B组予伊马替尼(20 mg·kg^(-1))+华法林(2 mg·kg^(-1)),C组予瑞戈非尼(10 mg·kg^(-1))+华法林(2 mg·kg^(-1))。通过眼眶后静脉丛采集大鼠血液样本,采用高效液相色谱串联质谱(HPLC-MS/MS)法测定血浆中(S)-华法林、(R)-华法林、(S)-7-羟基华法林和(R)-10(R)-羟基华法林的浓度,并采用非房室模型分析(NCA)计算药动学参数。结果 与A组比较,B组血浆中(R)-华法林的峰浓度(C_(max))及其代谢产物(R)-10(R)-羟基华法林的Cmax更低(P<0.05);C组血浆中(S)-华法林的Cmax、(S)-华法林达峰时间(T_(max))和(R)-10(R)-羟基华法林T_(max)更低(P<0.05);B组和C组的华法林对映体及其主要代谢产物的消除半衰期(t_(1/2))和血浆暴露量(AUC_(0-t)、AUC_(0-∞))与A组比较差异无统计学意义(P>0.05)。结论 伊马替尼和瑞戈非尼在体内会影响华法林对映体及其主要羟基化代谢产物的药动学过程,临床使用华法林时需考虑药物相互作用,保障临床安全、合理用药。
AIM To investigate the in vivo pharmacokinetic drug-drug interactions between imatinib,regorafenib and warfarin,and to evaluate their effects on the pharmacokinetics of warfarin.METHODSSA total of 18 Sprague-Dawley rats were randomly assigned to 3 groups(n=6 per group):group A received normal saline(10 mL·kg^(-1))plus warfarin(2 mg·kg^(-1)),group B received imatinib(20 mg kg)plus warfarin(2 mgkg'),and group C received regorafenib(10 mg·kg^(-1))plus warfarin(2 mg·kg^(-1)).Blood samples were collected via the retro-orbital venous plexus.Plasma concentrations of(S)-warfarin,(R)-warfarin,(S)-7-OH-warfarin,and(R)-10(R)-OH-warfarin were measured by highperformance liquid chromatography-tandem mass spectrometry(HPLC-MS/MS).Pharmacokinetic parameters were calculated using non-compartmental analysis(NCA).RESULTS Compared with the group A,the group B significantly reduced the peak plasma concentration(Cmax)of(R)-warfarin(P<0.05)and its metabolite(R)-10(R)-hydroxywarfarin(P<0.05).In contrast,the group C significantly increased the Cmax of(S)-warfarin(P<0.05),and shortened the time to peak(Tmax)of(S)-warfarin and(R)-10(R)-hydroxywarfarin(P<0.05).However,compared with the group A,no significant changes were observed in the elimination half-life(t_(1/2))and plasma exposure(AUC_(0-t),AUC_(0-∞))of the warfarin enantiomers and their major metabolites in the groups B and C(P>0.05).CONCLUSION Imatinib and regorafenib could influence the pharmacokinetics of warfarin enantiomers and their major hydroxylated metabolites in vivo,providing reference data for the safe and rational clinical use of these drugs.
作者
金莎莎
杨庆
方铂钰
林厚文
蔡卫民
JIN Shasha;YANG Qing;FANG Boyu;LIN Houwen;CAI Weimin(Department of Pharmacy,Renji Hospital,Shanghai Jiao Tong University School of Medicine,Shanghai 200127,China;Department of Clinical Pharmacy and Drug Administration,School of Pharmacy,Fudan University,Shanghai 201203,China)
出处
《中国临床药学杂志》
2025年第7期481-487,共7页
Chinese Journal of Clinical Pharmacy
基金
国家自然科学基金面上项目(编号81973389)。
关键词
华法林
伊马替尼
瑞戈非尼
药动学相互作用
warfarin
imatinib
regorafenib
pharmacokinetic drug-drug interactions
