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Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats
Li, Xin-gang2; Li, Liang2; Zhou, Xuan2; Chen, Ye2; Ren, Yu-peng2; Zhou, Tian-yan1,2; Lu, Wei1,2
关键词Exenatide Type 2 Diabetes Insulin Glucose Pharmacokinetic/pharmacodynamic Effect Compartment Indirect Response Model Nonmem
刊名ACTA PHARMACOLOGICA SINICA
2012-11-01
DOI10.1038/aps.2012.33
33期:11页:1379-1386
收录类别SCI
文章类型Article
WOS标题词Science & Technology
类目[WOS]Chemistry, Multidisciplinary ; Pharmacology & Pharmacy
研究领域[WOS]Chemistry ; Pharmacology & Pharmacy
关键词[WOS]GLUCAGON-LIKE PEPTIDE-1 ; INSULIN-SECRETION ; EXENDIN-4 ; PHARMACODYNAMICS ; PHARMACOKINETICS
英文摘要

Aim: To quantitatively evaluate the blood glucose-lowering effect of exenatide in diabetic rats.

Methods: Male Harlan-Sprague-Dawley rats were treated with high-fat diet/streptozotocin to induce type 2 diabetes. After subcutaneous administration of a single dose of exenatide (4.2, 42, or 210 mu g/kg), serum exenatide, insulin concentration and blood glucose were measured. The pharmacokinetics of exenatide was characterized by a two-compartment model with first-order absorption. Insulin turnover was characterized by an effect compartment and indirect response combined model. Glucose turnover was described using an indirect response model with insulin (in effect compartment) stimulating glucose disposition and insulin (in insulin compartment) inhibiting glucose production simultaneously. The model parameters were estimated using nonlinear mixed-effects model program. Visual predictive check and model evaluation were used to make assessments.

Results: Exenatide exhibited rapid absorption with k(a)=4.45 h(-1), and the two-compartment model well described its pharmacokinetic profile. For the pharmacodynamic model, exenatide increased insulin release with the estimated S-m1 of 0.822 and SC50 of 4.02 mu g/L. It was demonstrated that insulin stimulated glucose dissipation (S-m2=0.0513) and inhibited the production of glucose (I-m=0.0381). Visual predictive check and model evaluation study indicated that a credible model was developed.

Conclusion: The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model.

语种英语
WOS记录号WOS:000310778400007
项目编号2009ZX09301-010
资助机构Ministry of Science and Technology of China (Peking University New Drug Research &amp ; Development Platform)
引用统计
被引频次:10[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/400002259/56596
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
Li, Xin-gang,Li, Liang,Zhou, Xuan,et al. Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats[J]. ACTA PHARMACOLOGICA SINICA,2012,33(11):1379-1386.
APA Li, Xin-gang.,Li, Liang.,Zhou, Xuan.,Chen, Ye.,Ren, Yu-peng.,...&Lu, Wei.(2012).Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats.ACTA PHARMACOLOGICA SINICA,33(11),1379-1386.
MLA Li, Xin-gang,et al."Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats".ACTA PHARMACOLOGICA SINICA 33.11(2012):1379-1386.
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