Pharmacokinetic/Pharmacodynamic Analysis of Metformin using Different Models in Diabetic Rats

Abstract

Backgroud and study aims: Metformin is believed to be the most widely used hypoglycemic agent in the world. We aimed to investigate the pharmacokinetic/pharmacodynamics properties of metformin in diabetic rats using different pharmacodynamics models, and compare models fitting quality.

Methods: Streptozotocin diabetic rats received metformin via oral route and blood samples were collected at the schedule times. Plasma metformin concentration and blood glucose levels were measured. Pharmacokinetic/pharmacodynamic analysis was conducted using nonlinear mixed-effects modeling. Metformin pharmacokinetics was described using a 2-compartmental model with first-order absorption. Five pharmacodynamic models were employed to characterize the hypoglycemic effect of metformin: effect-compartment model (I), indirect response (IDR) model with stimulating the loss of blood glucose (II), IDR model with inhibiting the production of blood glucose (III), combined effect-compartment/IDR model with stimulating the removal of blood glucose (IV) and combined effect-compartment/IDR model with inhibiting the input of blood glucose (V). Akaike’s information criterion (AIC) values and goodness-of-fit were applied to estimate the pharmacodynamic model.

Results: The Model V provided a more appropriate and good-fitting pharmacodynamic characterization of metformin than the others. All the parameter values were estimated with good precision and model evaluation by visual predictive check suggested that the proposed model is robust.

Conclusion: The proposed pharmacokinetic/pharmacodynamic model may be useful in the description for the relationship between metformin concentration and its glucose-lowering effects. For metformin, biophase distribution and inhibiting the production of glucose may be existed simultaneously.

Key words

pharmacokinetic/pharmacodynamic modeling - metformin - effect-compartment - indirect response - glucose-lowering effect

• References

• 1 American Diabetes A . Standards of medical care in diabetes – 2009. Diabetes Care 2009; 32 (Suppl. 01) S13-S61
• 2 Inzucchi SE, Bergenstal RM, Buse JB et al. Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care 2012; 35: 1364-1379
• 3 Hundal RS, Krssak M, Dufour S et al. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes 2000; 49: 2063-2069
• 4 Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med 2002; 137: 25-33
• 5 Morioka K, Nakatani K, Matsumoto K et al. Metformin-induced suppression of glucose-6-phosphatase expression is independent of insulin signaling in rat hepatoma cells. Int J Mol Med 2005; 15: 449-452
• 6 Wilcock C, Bailey CJ. Reconsideration of inhibitory effect of metformin on intestinal glucose absorption. J Pharm Pharmacol 1991; 43: 120-121
• 7 Bailey CJ, Turner RC. Metformin. N Engl J Med 1996; 334: 574-579
• 8 Collier CA, Bruce CR, Smith AC et al. Metformin counters the insulin-induced suppression of fatty acid oxidation and stimulation of triacylglycerol storage in rodent skeletal muscle. Am J Physiol Endocrinol Metab 2006; 291: E182-E189
• 9 Musi N, Hirshman MF, Nygren J et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 2002; 51: 2074-2081
• 10 Viollet B, Foretz M. Revisiting the mechanisms of metformin action in the liver. Ann Endocrinol (Paris) 2013; 74: 123-129
• 11 Felmlee MA, Morris ME, Mager DE. Mechanism-based pharmacodynamic modeling. Methods Mol Biol 2012; 929: 583-600
• 12 Stepensky D, Friedman M, Raz I et al. Pharmacokinetic-pharmacodynamic analysis of the glucose-lowering effect of metformin in diabetic rats reveals first-pass pharmacodynamic effect. Drug Metab Dispos 2002; 30: 861-868
• 13 Lehr T, Staab A, Tillmann C et al. Contribution of the active metabolite M1 to the pharmacological activity of tesofensine in vivo: a pharmacokinetic-pharmacodynamic modelling approach. Br J Pharmacol 2008; 153: 164-174
• 14 van Steeg TJ, Freijer J, Danhof M et al. Pharmacokinetic-pharmacodynamic modelling of S(-)-atenolol in rats: reduction of isoprenaline-induced tachycardia as a continuous pharmacodynamic endpoint. Br J Pharmacol 2007; 151: 356-366
• 15 Dayneka NL, Garg V, Jusko WJ. Comparison of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm 1993; 21: 457-478
• 16 Hong Y, Rohatagi S, Habtemariam B et al. Population exposure-response modeling of metformin in patients with type 2 diabetes mellitus. J Clin Pharmacol 2008; 48: 696-707
• 17 Sun L, Kwok E, Gopaluni B et al. Pharmacokinetic-Pharmacodynamic Modeling of Metformin for the Treatment of Type II Diabetes Mellitus. Open Biomed Eng J 2011; 5: 1-7
• 18 Chae JW, Baek IH, Lee BY et al. Population PK/PD analysis of metformin using the signal transduction model. Br J Clin Pharmacol 2012; 74: 815-823
• 19 Chen Y, Li H, Xu J et al. Determination of metformin in diabetic rat plasma by an improved ion-pair high-performance liquid chromatography: application to a pharmacokinetic study. J Chin Pharm Sci 2012; 21: 211-218
• 20 Li XG, Li L, Zhou X et al. Pharmacokinetic/pharmacodynamic studies on exenatide in diabetic rats. Acta Pharmacol Sin 2012; 33: 1379-1386
• 21 Wilcock C, Bailey CJ. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 1994; 24: 49-57
• 22 Sharma A, Jusko WJ. Characterization of four basic models of indirect pharmacodynamic responses. J Pharmacokinet Biopharm 1996; 24: 611-635
• 23 Cai NF, Cheng ZN, Zi Y et al. Pharmacodynamic analysis of intravenous recombinant urate oxidase using an indirect pharmacological response model in healthy subjects. Acta Pharmacol Sin 2014; 35: 1447-1452
• 24 Shen J, Xiao J, Pickthorn K et al. A pharmacokinetic/pharmacodynamic model for AMG 416, a novel calcimimetic peptide, following a single intravenous dose in healthy subjects. J Clin Pharmacol 2014; 54: 1125-1133
• 25 Ternant D, Ducourau E, Fuzibet P et al. Pharmacokinetics and concentration-effect relationship of adalimumab in rheumatoid arthritis. Br J Clin Pharmacol 2015; 79: 286-297
• 26 Burcelin R. The antidiabetic gutsy role of metformin uncovered?. Gut 2014; 63: 706-707
• 27 Madiraju AK, Erion DM, Rahimi Y et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 2014; 510: 542-546
• 28 Miller RA, Chu Q, Xie J et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 2013; 494: 256-260
• 29 He L, Sabet A, Djedjos S et al. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 2009; 137: 635-646