Free interstitial levels of metformin in the liver of healthy and diabetic Wistar rats
DOI:
https://doi.org/10.1590/s2175-97902022e19674%20Keywords:
Metformin, Microdialysis, Pharmacokinetics, Experimental diabetesAbstract
In the present study, free interstitial levels reached by metformin in the liver were investigated in control and diabetic rats by microdialysis. Firstly, a bioanalytical method using an HPLC-UV system to determine the drug concentration in microdialysis samples was validated. The blood glucose levels and biochemical parameters were investigated in control and diabetic animals. Following that, both groups received a dose of 50 mg/kg of metformin iv bolus and the free interstitial levels reached in the liver were assessed by microdialysis. The method was validated according to FDA guidelines being suitable to quantify free concentrations of metformin in the liver of control and diabetics rats. Free exposure to metformin was similar in control and diabetic animals: AUC0-∞ 118.50 ± 40.18 vs 112.93 ± 50.25 µg.h/mL, respectively. The half-life in tissue was similar to that described in the literature for plasma. Hence diabetes induced by streptozotocin after administration of nicotinamide in our study did not damage the renal and hepatic function of the animals. The levels reached in the liver were 1.6 times higher than the free plasma concentrations, demonstrating higher liver penetration of metformin. This is the first investigation in liver interstitial concentration of metformin in control and diabetic rats.
Downloads
References
Araujo BV, Silva CF, Haas SE, Dalla Costa T. Microdialysis as a tool to determine free kidney levels of voriconazole in rodents: a model to study the technique feasibility for a moderately lipophilic drug. J Pharm Biomed Anal. 2008;47(4-5):876-81.
Azeredo FJ, Dalla Costa T, Derendorf H. Role of microdialysis in pharmacokinetics and pharmacodynamics: Current status and future directions. Clin Pharmacokinet. 2014;53(3):205-12.
Beckmann R. Absorption, distribution in the organism and elimination of metformin. Diabetologia. 1969;5(5):318-24.
Choi YH, Kim SG, Lee MG. Dose-independent pharmacokinetics of metformin in rats: Hepatic and gastrointestinal first-pass effects. J Pharm Sci. 2006;95(11):2543-52.
Choi YH, Lee DC, Lee I, Lee MG. Changes in metformin pharmacokinetics after intravenous and oral administration to rats with short-term and long-term diabetes induced by streptozotocin. J Pharm Sci. 2008;97(12):5363-75.
Food and Drug Administration. Guidance for industry: Bioanalytical method validation. Available from: http://www.fda.gov/downloads/Drugs/Guidance/ucm070107.pdf
» http://www.fda.gov/downloads/Drugs/Guidance/ucm070107.pdf
Ghasemi A, Khalifi S, Jedi S. Streptozotocin-nicotinamide- induced rat model of type 2 diabetes (review). Acta Physiol Hung. 2014;101(4):408-20.
Graham GG, Punt J, Arora M, Day RO, Doogue MP, Duong JK, et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet. 2011;50(2):81-98.
Grover B, Buckley D, Buckley AR, Cacini W. Reduced expression of organic cation transporters rOCT1 and rOCT2 in experimental diabetes. J Pharmacol Exp Ther. 2004;308(3):949-56.
Higgins JW, Bedwell DW, Zamek-gliszczynski MJ. Ablation of Both Organic Cation Transporter (Oct) 1 and Oct2 Alters Metformin Pharmacokinetics but Has No Effect on Tissue Drug Exposure and Pharmacodynamics. Drug Metab Dispos. 2012;40(6):1170-7.
Lange ECM. Recovery and calibration techniques: toward quantitative microdialysis. In: Müller M (Ed.) Microdialysis in Drug Development. New York: Springer-Verlag; 2013; p.13-33.
Lee JH, Yang SH, Oh JM, Lee MG. Pharmacokinetics of drugs in rats with diabetes mellitus induced by alloxan or streptozocin: comparison with those in patients with type I diabetes mellitus. J Pharm Pharmacol. 2010;62(1):1-23.
Lee MG, Choi YH, Lee I. Effects of diabetes mellitus induced by alloxan on the pharmacokinetics of metformin in rats: restoration of pharmacokinetic parameters to the control state by insulin treatment. J Pharm Pharm Sci. 2008;11(1):88-103.
Liang X, Giacomini KM. Transporters Involved in Metformin Pharmacokinetics and Treatment Response. J Pharm Sci. 2017;106(9):2245-2250.
Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillarire-Buys D, et al. Development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes. 1998;47(February):224-9.
Mouton JW, Theuretzbacher U, Craig WA, Tulkens PM, Derendorf H, Cars O. Tissue concentrations: do we ever learn? J Antimicrob Chemother. 2008;61(2):235-7.
National Research Council (US) Guide for the Care and Use of Laboratory Animals. 8th Ed. Washington: The National Academies Press; 2011. Available from: http://www.ncbi.nlm.nih.gov/books/NBK54050/
» http://www.ncbi.nlm.nih.gov/books/NBK54050/
Nowicki MT, Aleksunes LM, Sawant SP, Dnyanmote AV, Mehendale HM, Manautou JE. Renal and hepatic transporter expression in type 2 diabetic rats. Drug Metab Lett. 2008;2(1):11-7.
Plock N, Kloft C. Microdialysis--theoretical background and recent implementation in applied life-sciences. Eur J Pharm Sci Off J Eur Fed Pharm Sci. 2005;25(1):1-24.
Pries AR, Kuebler WM. Normal endothelium. In: Moncada S, Higgs, A (Ed). The vascular endothelium I. Berlin, Heidelberg:Springer; 2006;p.1-40.
Radenković M, Stojanović M, Prostran M. Experimental diabetes induced by alloxan and streptozotocin: The current state of the art. J Pharmacol Toxicol Methods. 2016;78:13-31.
Slitt AL, Cherrington NJ, Hartley DP, Leazer TM, Klaassen CD. Tissue distribution and renal developmental changes in rat organic cation transporter mRNA levels. Drug Metab Dispos. 2002;30(2):212-9.
Sogame Y, Kitamura A, Yabuki M, Komuro S. Liver uptake of Biguanides in rats. Biomed Pharmacother. 2011;65(6):451-5.
Srinivas NR. Strategies for preclinical pharmacokinetic investigation in streptozotocin-induced diabetes mellitus (DMIS) and alloxan-induced diabetes mellitus (DMIA) rat models: case studies and perspectives. Eur J Drug Metab Pharmacokinet. 2015;40(1):1-12.
Szkudelski T. Streptozotocin-nicotinamide-induced diabetes in the rat. Characteristics of the experimental model. Exp Biol Med. 2012;237(5):481-90.
Terada T, Masuda S, Asaka J-I, Tsuda M, Katsura T, Inui K. Molecular cloning, functional characterization and tissue distribution of rat H+/organic cation antiporter MATE1. Pharm Res. 2006;23(8):1696-701.
Downloads
Published
Issue
Section
License
Copyright (c) 2022 Brazilian Journal of Pharmaceutical Sciences
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on-line journal has open and free access.
How to Cite
Funding data
-
Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul
Grant numbers 159722/2013-6 -
Conselho Nacional de Desenvolvimento Científico e Tecnológico
Grant numbers 0450-2251/14-6
