Evaluation of drug-drug interaction on concomitant administration of anti-diabetics and hypolipidemics in in vivo models

Paper Details

Research Paper 01/01/2019
Views (267) Download (16)

Evaluation of drug-drug interaction on concomitant administration of anti-diabetics and hypolipidemics in in vivo models

Rania Indu, Anjan Adhikari, Piyali Basak, Dipankar Banerjee, Tapas Kumar Sur
Int. J. Biosci.14( 1), 317-327, January 2019.
Certificate: IJB 2019 [Generate Certificate]


Diabetes mellitus is a multifactorial pathological condition, often associated with co-morbid condition of hyperlipidemia. Anti-diabetics and hypolipidemics are thus co-prescribed. Now, this use of multiple drugs or polypharmacy, however, increases the propensity of drug-drug interactions and adverse drug reactions. Present study was aimed to evaluate the effect of concomitant therapy of anti-diabetics and hypolipidemics on animal models induced with comorbid conditions of diabetes and hyperlipidemia. Diabetes was induced by Streptozotocin and Nicotinamide and hyperlipidemia was induced by High Fat Diet. Comorbid condition of both diabetes and hyperlipidemia was developed in rats. The rats were treated with antidiabetic drug Metformin and hypolipidemic drug Atorvastatin for 28 days. The safety and efficacy of concomitant therapy was evaluated by different biomarkers in serum and antioxidant levels in hepatic and renal tissues, collected from the rats. It was observed that concomitant therapy of Metformin and Atorvastatin was able to restore the blood glucose and triglyceride level by 69.93% and 54.61%, respectively. Concomitant therapy, however, was accompanied by increased oxidative stress in tissues, characterized by altered antioxidant levels. The hepatic and renal glutathione was diminished by 67.6% and 79.7% respectively, whereas, malondialdehyde level was enhanced by 31.7% and 83.3%, indicating oxidative stress induced tissue damage. This preliminary study was an attempt to mimic the comorbid diseased condition in animal model and to evaluate the safety and efficacy of concomitant therapy in animals that can be translated in human system to optimize therapeutic regimen.


Adela R, Nethi SK, Bagul PK, Barui AK, Mattapally S, Kuncha M. 2015. Hyperglycaemia Enhances Nitric Oxide Production in Diabetes: A Study from South Indian Patients. PLoS ONE 10, e0125270. http://dx.doi.org/10.1371/journal.pone.0125270.

Akbarzadeh A, Norouzian D, Mehrabi MR, Jamshidi S, Farhangi A, Allah Verdi A. 2007. Induction of diabetes by Streptozotocin in rats. Indian Journal of Clinical Biochemistry 22, 60-64. http://dx.doi.org/10.1007/BF02913315.

Anitha N, Rao JV, Kavimani S, Himabindu V. 2008. Pharmacodynamic Drug Interaction of Metformin with Statins in Rats. Journal of Pharmacology and Toxicology 3, 409-413. http://dx.doi.org/10.3923/jpt.2008.409.413

Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C. 2005. Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14. randomised trials of statins. Lancet 366, 1267–1278. http://dx.doi.org/10.1016/S0140-6736(05)67394-1.

Buege JA, Aust SD. 1978. Microsomal lipid peroxidation. Methods in Enzymology 52, 302–310. http://dx.doi.org/10.1016/S0076-6879(78)52032-6

Committee for the Purpose of Control and Supervision on Experiments on Animals. 2003. CPCSEA guidelines for laboratory animal facility. Indian Journal of Pharmacology 35, 257.

Ding Y, Zou J, Li Z, Tian J, Abdelalim S, Du F. 2011. Study of Histopathological and Molecular Changes of Rat Kidney under Simulated Weightlessness and Resistance Training Protective Effect. PLoS ONE 6, e20008. http://dx.doi.org/10.1371/journal.pone.0020008.

Galani V, Vyas M. 2010. In vivo and In vitro Drug Interactions Study of Glimepride with Atorvastatin and Rosuvastatin. Journal of Young Pharmacists 2, 196-200. http://dx.doi.org/10.4103/0975-1483.63169

Indu R, Adhikari A, Basak P, Sur TK, Samadder S, Das AK. 2018. Evaluation of Drug-Drug Interaction Using In Vitro Methods. 7th Annual International Conference & Exhibition, Society Pharmaceutical Education & Research [SPER] Times 6, 41 (PH-02).

Indu R, Adhikari A, Maisnam I, Basak P, Sur TK, Das AK. 2017. Polypharmacy and Comorbidity Status in the Treatment of Type 2 Diabetic Patients attending a Tertiary Care Hospital: An Observational and Questionnaire-based Study. Perspectives in Clinical Research 9, 139-144. http://dx.doi.org/10.4103/picr.PICR_81_17

Joshi SR, Anjana RM, Deepa M, Pradeepa R, Bhansali A, Dhandania VK. 2014. Prevalence of Dyslipidemia in Urban and Rural India: The ICMR–INDIAB Study. PLoS. ONE 9, e96808. http://dx.doi.org/10.1371/journal.pone.0096808.

Kaveeshwar SA, Cornwall J. 2014. The current state of diabetes mellitus in India. Australasian Medical Journal 7, 45-48. http://dx.doi.org/10.4066/AMJ.2013.1979

Lawrence R, Burk R. 1976. Glutathione peroxidase activity in selenium-deficient rat liver. Biochemical and Biophysical Research Communications 71, 952–958. http://dx.doi.org/10.1016/0006-291X(76)90747-6

Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. 1951. Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry 193, 265–275.

Maithili V, Dhanabal SP, Mahendran S, Vadivelan R. 2011. Antidiabetic activity of ethanolic extract of tubers of Dioscoreaalata in alloxan induced diabetic rats. Indian Journal of Pharmacology 43, 455-459. http://dx.doi.org/10.4103/0253-7613.83121

Mansor LS, Gonzalez ER, Cole MA, Tyler DJ, Beeson JH, Clarke K. 2013. Cardiac metabolism in a new rat model of type 2 diabetes using high-fat diet with low dose streptozotocin. Cardiovascular Diabetology 12, 136.http://dx.doi.org/10.1186/1475-2840-12-136.

Marques C, Meireles M, Norberto S, Leite J, Freitas J, Pestana D. 2016. High-fat diet-induced obesity Rat model: a comparison between Wistar and Sprague-Dawley Rat. Adipocyte 5, 11-21. http://dx.doi.org/10.1080/21623945.2015.1061723.

Maruthappan V, Shree KS. 2010. Effects of Phyllanthusreticulatus on lipid profile and oxidative stress in hypercholesterolemic albino rats. Indian Journal of Pharmacology 42, 388-391. http://dx.doi.org/10.4103/0253-7613.71923

Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillaire-Buys D. 1998. Experimental NIDDM: Development of a new model in adult rats administered streptozotocin and nicotinamide. Diabetes 47, 224–229. http://dx.doi.org/10.2337/diab.47.2.224

Mithal A, Majhi D, Shunmugavelu M, Talwarkar PG, Vasnawala H, Raza AS. 2014. Prevalence of dyslipidemia in adult Indian diabetic patients: A cross sectional study (SOLID). Indian Journal of Endocrinology and Metabolism 18, 642-647. http://dx.doi.org/10.4103/2230-8210.139220.

Mooradian AD. 2009. Dyslipidemia in type 2 diabetes mellitus. Nature clinical practice. Endocrinology andMetabolism 5, 150–159. http://dx.doi.org/10.1038/ncpendmet1066.

Moshage H, Kok B, Huizenga JR, Jansen PL. 1995. Nitrite and nitrate determinations in plasma: critical evaluation. Clinical Chemistry 41, 892–896.

Muruganandan S,  Srinivasan K,  Gupta S,  Gupta PK,  Lal J. 2005. Effect of mangiferin on hyperglycemia and atherogenicity in streptozotocin diabetic rats. Journal of Ethnopharmacology 97, 497-501. http://dx.doi.org/10.1016/j.jep.2004.12.010.

Patro G, Bhattamisra SK, Mohanty BK, Sahoo HB. 2016. In vitro and In vivo Antioxidant Evaluation and Estimation of Total Phenolic, Flavonoidal Content of Mimosa pudica L. Pharmacognosy Research 8, 22–28. http://dx.doi.org/10.4103/0974-8490.171099.

Payne RA, Avery AJ. 2011. Polypharmacy: one of the greatest prescribing challenges in general practice. British Journal of General Practice 61, 83-84. http://dx.doi.org/10.3399/bjgp11X556146

Rahimi-Madiseh M, Karimian P, Kafeshani M, Rafieian-Kopaei M. 2017. The effects of ethanol extract of Berberis vulgaris fruit on histopathological changes and biochemical markers of the liver damage in diabetic rats.  Iranian Journal of Basic Medical Sciences 20, 552-556. http://dx.doi.org/10.22038/IJBMS.2017.8681

Sadi G, Baloğlu MC, Pektaş MB. 2015. Differential Gene Expression in Liver Tissues of Streptozotocin-Induced Diabetic Rats in Response to Resveratrol Treatment. PLoS ONE 10, e0124968. http://dx.doi.org/10.1371/journal.pone.0124968.

Schofield JD, Liu Y, Rao-Balakrishna P, Malik RA, Soran H. 2016. Diabetes Dyslipidemia. Diabetes Therapy 7, 203-219.

Singh R, Bhardwaj P, Sharma P. 2013. Antioxidant and toxicological evaluation of Cassia sopherain streptozotocin-induced diabetic Wistar rats. Pharmacognosy Research 5, 225-232. http://dx.doi.org/10.4103/0974-8490.118767.

Tangvarasittichai S. 2015. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World Journal of Diabetes 6, 456-480. http://dx.doi.org/10.4239/wjd.v6.i3.456.

Venkateshan S, Subramaniyan V, Chinnasamy V, Chandiran S. 2016.  Anti-oxidant and anti-hyperlipidemic activity ofHemidesmusindicusin rats fed with high-fat diet. Avicenna Journal of Phytomedicine 6, 516-525. http://dx.doi.org/10.22038/AJP.2016.6466

Widyawati T, Adlin Yusoff N, Asmawi MZ, Ahmad M. 2015. Antihyperglycemic Effect of Methanol Extract of Syzygiumpolyanthum (Wight.) Leaf in Streptozotocin-Induced Diabetic Rats. Nutrients 7, 7764-7780. http://dx.doi.org/10.3390/nu7095365.

Yan L, Xu MT, Yuan L, Chen B, Xu ZR, Guo QH. 2016. Prevalence of dyslipidemia and its control in type 2 diabetes: A multicenter study in endocrinology clinics of China. Journal of Clinical Lipidology 10, 150–160. http://dx.doi.org/10.1016/j.jacl.2015.10.009.

Yu J, Yang X, Yang X, Yang M, Wang P, Yang Y. 2018. Nonylphenol aggravates non-alcoholic fatty liver disease in high sucrose-high fat diet-treated rats. Scientific Reports 8, 3232. http://dx.doi.org/10.1038/s41598-018-21725-y.

Zarei A, Changizi Ashtiyani S, Taheri S, Rasekh F. 2014. Comparison between effects of different doses of Melissa officinalis and atorvastatin on the activity of liver enzymes in hypercholesterolemia rats. Avicenna Journal of Phytomedicine 4, 15-23.