|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|
|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|
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.
|资助机构||Ministry of Science and Technology of China (Peking University New Drug Research & ; Development Platform)|
|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
|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.|