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Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model
Wu, Qiong2; Li, Meng-yao2; Li, Han-qing2; Deng, Chen-hui2; Li, Liang1,2; Zhou, Tian-yan1,2; Lu, Wei1,2
关键词Non-small-cell Lung Cancer Anticancer Drug Erlotinib Epidermal Growth Factor Receptor Pharmacokinetic-pharmacodynamic Modeling Human Tumor Xenograft Mouse Model
刊名ACTA PHARMACOLOGICA SINICA
2013-11-01
DOI10.1038/aps.2013.101
34期:11页:1427-1436
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
资助者Innovation Team of Ministry of Education ; National Natural Science Foundation of China ; Innovation Team of Ministry of Education ; National Natural Science Foundation of China
研究领域[WOS]Chemistry ; Pharmacology & Pharmacy
关键词[WOS]GROWTH-FACTOR RECEPTOR ; TYROSINE KINASE INHIBITOR ; BIOMARKER RESPONSE ; CARCINOMA ; MALIGNANCIES ; EXPRESSION ; PREDICTION ; THERAPY ; TARGET ; HEAD
英文摘要

Aim: Erlotinib is used to treat non-small-cell lung cancer (NSCLC), which targets epidermal growth factor receptor (EGFR) tyrosine kinase. The aim of this study was to investigate the relationship between erlotinib plasma concentrations and phosphorylated EGFR (pEGFR) levels, as well as the relationship between pEGFR levels and tumor growth inhibition in a human non-small-cell lung cancer xenograft mouse model.

Methods: Female BALB/c nude mice were implanted with the human NSCLC cell line SPC-A-1. The animals were given via gavage a single dose of erlotinib (4, 12.5, or 50 mg/kg). Pharmacokinetics of erlotinib was determined using LC-MS/MS. Tumor volume and pEGFR levels in tumor tissues were measured at different time points after erlotinib administration. The levels of pEGFR in tumor tissues was detected using Western blotting and ELISA assays.

Results: The pharmacokinetics of erlotinib was described by a two-compartment model with first order extravascular absorption kinetics. There was a time delay of approximately 2 h between erlotinib plasma concentrations and pEGFR degradation. The time course of pEGFR degradation was reasonably fit by the indirect response model with a calculated IC50 value of 1.80 mu g/mL. The relationship between pEGFR levels and tumor volume was characterized by the integrated model with a K-bio value of 0.507 cm(3)/week, which described the impact of pEGFR degradation on tumor growth.

Conclusion: The pharmacokinetic/pharmacodynamic properties of erlotinib in a human tumor xenograft model were described by the indirect response model and integrated model, which will be helpful in understanding the detailed processes of erlotinib activity and determining an appropriate dosing regimen in clinical studies.

语种英语
所属项目编号BMU20110263E ; 81273583
资助者Innovation Team of Ministry of Education ; National Natural Science Foundation of China ; Innovation Team of Ministry of Education ; National Natural Science Foundation of China
WOS记录号WOS:000326680500009
引用统计
被引频次:5[WOS]   [WOS记录]     [WOS相关记录]
文献类型期刊论文
条目标识符http://ir.bjmu.edu.cn/handle/400002259/56535
专题北京大学药学院_药剂学系
作者单位1.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China
2.Peking Univ, Hlth Sci Ctr, Sch Pharmaceut Sci, Dept Pharmaceut, Beijing 100191, Peoples R China
推荐引用方式
GB/T 7714
Wu, Qiong,Li, Meng-yao,Li, Han-qing,et al. Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model[J]. ACTA PHARMACOLOGICA SINICA,2013,34(11):1427-1436.
APA Wu, Qiong.,Li, Meng-yao.,Li, Han-qing.,Deng, Chen-hui.,Li, Liang.,...&Lu, Wei.(2013).Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model.ACTA PHARMACOLOGICA SINICA,34(11),1427-1436.
MLA Wu, Qiong,et al."Pharmacokinetic-pharmacodynamic modeling of the anticancer effect of erlotinib in a human non-small cell lung cancer xenograft mouse model".ACTA PHARMACOLOGICA SINICA 34.11(2013):1427-1436.
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