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学科主题: 药学
题名:
Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats
作者: 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
发表日期: 2012-11-01
DOI: 10.1038/aps.2012.33
卷: 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
所属项目编号: 2009ZX09301-010
项目资助者: Ministry of Science and Technology of China (Peking University New Drug Research &amp ; Development Platform)
WOS记录号: WOS:000310778400007
Citation statistics:
内容类型: 期刊论文
URI标识: http://ir.bjmu.edu.cn/handle/400002259/56596
Appears in Collections:北京大学药学院_药剂学系_期刊论文

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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

Recommended Citation:
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.
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