抗肿瘤化合物TM208在乳腺癌中抑制雌激素的药代动力学-药效学研究
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摘要
目的建立抗肿瘤化合物TM208在荷瘤鼠体内的药代动力学/药效学(PK/PD)模型,研究其在乳腺癌肿瘤内对雌激素水平的抑制作用,并探究通过建模定量描述连续给药所引起的肿瘤耐药性现象。方法建立异种移植人乳腺癌MCF-7细胞的BALB/c裸鼠移植瘤模型,连续灌胃给药TM208(150mg·kg~(-1)·d~(-1))及溶剂(空白对照组)18 d。用酶联免疫法(ELISA)测定健康裸鼠乳腺组织以及TM208给药前和给药后荷瘤鼠肿瘤组织中雌激素含量随时间变化的过程,同时考察TM208的体内PK过程。用一室药代动力学模型来拟合体内TM208的PK特征,并用间接效应模型结合耐药模型描述了雌激素水平随时间的变化过程。结果 TM208对于雌激素的抑制作用会逐渐减弱,推测可能与乳腺癌肿瘤的耐药性有关。而耐药性的生成速率为0.68 h~(-1)。结论所建立的PK/PD模型能够定量描述TM208对肿瘤内雌激素的抑制作用,而应用耐药模型能够预测乳腺癌肿瘤耐药性的产生。
Objective To investigate the profiles of resistance following continuous treatment with TM208 using pharmacokinetics/pharmacodynamic( PK/PD) model,as well as to characterize the estrogen levels in hibition in human breast cancer xenograft mice. Methods MCF-7 xenograftnudemice were given TM208( 150 mg·kg~(-1)·d~(-1)) or vehicle orally for 18 days. The concentrations of estrogen were measured using the human estrogen ELISA kit. The pharmacokinetics and pharmacodynamics of TM208 were evaluated after administration. A one-compartment model with first order absorption was developed to describe the pharmacokinetics of TM208,and the time course of estrogen degradation was characterized by the indirect response model. Tolerance model was used to describe drug resistance of tumor. Results The simulation results showed that the inhibitory effects of TM208 on estrogen may decrease after continuous administration,and the KTO was 0. 68 h~(-1). Conclusion The established PK/PD model allowed a better understanding of the role of estrogen inhibition in breast cancer treatment with TM208. Simulation based on the estrogen model allowed prediction of the detailed processes of TM208 effects on estrogen. Furthermore,the tolerance model-based modeling and simulation methods provided an option for thedescription and prediction of estrogen resistance.
Objective To investigate the profiles of resistance following continuous treatment with TM208 using pharmacokinetics/pharmacodynamic( PK/PD) model,as well as to characterize the estrogen levels in hibition in human breast cancer xenograft mice. Methods MCF-7 xenograftnudemice were given TM208( 150 mg·kg~(-1)·d~(-1)) or vehicle orally for 18 days. The concentrations of estrogen were measured using the human estrogen ELISA kit. The pharmacokinetics and pharmacodynamics of TM208 were evaluated after administration. A one-compartment model with first order absorption was developed to describe the pharmacokinetics of TM208,and the time course of estrogen degradation was characterized by the indirect response model. Tolerance model was used to describe drug resistance of tumor. Results The simulation results showed that the inhibitory effects of TM208 on estrogen may decrease after continuous administration,and the KTO was 0. 68 h~(-1). Conclusion The established PK/PD model allowed a better understanding of the role of estrogen inhibition in breast cancer treatment with TM208. Simulation based on the estrogen model allowed prediction of the detailed processes of TM208 effects on estrogen. Furthermore,the tolerance model-based modeling and simulation methods provided an option for thedescription and prediction of estrogen resistance.
引文
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[2]JI X W,LI R T,LI Z Q,et al.Inhibition of EGFR autophosphorylation plays an important role in the anti-breast cancer efficacy of the dithiocarbamate derivative TM208[J].Acta Pharmacol Sin,2014,35(2):239-247.
[3]JI X W,CHEN G P,SONG Y,et al.Intratumoral estrogen sulfotransferase induction contributes to the anti-breast cancer effects of the dithiocarbamate derivative TM208[J].Acta Pharmacol Sin,2015,36(10):1246-1255.
[4]JI X,CHEN Y,LI R,et al.A high-sensitivity LC-MS/MS method for the determination of 4-methyl-piperazine-1-carbodithioc acid 3-cyano-3,3-diphenylpropyl ester hydrochloride in rat plasma and its application to a pharmacokinetics study[J].Biomed Chromatogr,2012,26(10):1196-1201.
[5]JI X W,JI S M,LI R T,et al.Pharmacokinetic-pharmacodynamic modeling of the antitumor effect of TM208 and EGFR-TKI resistance in human breast cancer xenograft mice[J].Acta Pharmacol Sin,2016,37(6):825-833.
[6]AHLSTRM C,PELETIER L A,JANSSON-LFMARK R,et al.Feedback modeling of non-esterified fatty acids in rats after nicotinic acid infusions[J].J Pharmacokinet Pharmacodyn,2011,38(1):1-24.
[7]MANDEMA J W,WADA D R.Pharmacodynamic model for acute tolerance development to the electroencephalographic effects of alfentanil in the rat[J].J Pharmacol Exp Ther,1995,275(3):1185-1194.
[8]SHI J,BENOWITZ N L,DENARO C P,et al.Pharmacokineticpharmacodynamic modeling of caffeine:tolerance to pressor effects[J].Clin Pharmacol Ther,1993,53(1):6-14.