Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats.
OBJECTIVE
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 μg/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 SC(50) of 4.02 μg/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.


CONCLUSIONS
The glucose-lowering effect of exenatide in diabetic rats is reliably described and predicted by the combined effect compartment/indirect response model.
Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
Xin-gang
XG
Li
Liang
L
Li
Xuan
X
Zhou
Ye
Y
Chen
Yu-peng
YP
Ren
Tian-yan
TY
Zhou
Wei
W
Lu
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D059305:Diet, High-Fat; D004305:Dose-Response Relationship, Drug; D000077270:Exenatide; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D007328:Insulin / Q000097:blood; D008297:Male; D008954:Models, Biological; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D014688:Venoms / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D013311:Streptozocin; D000077270:Exenatide