Microbial Bioactives
Study of the Effects of Complexation of Lead with Metformin, Glimepiride, Vildagliptin and Dapagliflozin in Mice Model and Its Biological Implications
Fahima Aktar, Md. Zakir Sultan, Mohammad A. Rashid
Microbial Bioactives 3(1) 125-133 https://doi.org/10.25163/microbbioacts.31210910822111120
Submitted: 08 October 2020 Revised: 22 October 2020 Published: 11 November 2020
Lead–drug complexation alters therapeutic efficacy and induces toxicity, highlighting critical implications for environmental exposure, applied microbiology, and drug safety assessment.
Abstract
Background: Lead is a widespread environmental pollutant present in air, water, and soil, and its persistence in biologically active systems raises important concerns regarding human health, ecological stability, and chemical interactions with therapeutic agents. In contaminated environments, heavy metals may alter the physicochemical behavior and biological performance of pharmaceutical compounds, potentially influencing their efficacy and toxicity. Because such interactions are also relevant to microbiologically active food, water, and environmental systems, understanding lead–drug complex formation is of considerable applied significance. The present study investigated the formation of lead complexes with selected antidiabetic drugs and evaluated their biological consequences in vivo.
Methods: Four antidiabetic drugs—metformin, glimepiride, vildagliptin, and dapagliflozin—were reacted with metallic lead under different conditions to generate four complexes: Pb-metformin, Pb-glimepiride, Pb-vildagliptin, and Pb-dapagliflozin. Complex formation was confirmed by thin-layer chromatography (TLC), differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), and Fourier-transform infrared spectroscopy (FT-IR). The physiological effects of the synthesized complexes were then assessed in a mice model by measuring blood glucose, serum creatinine, and uric acid levels, followed by histopathological examination of liver and kidney tissues.
Results: Compared with their parent drugs, the lead-associated complexes showed markedly reduced glucose-lowering efficacy and significantly altered physiological responses. While metformin, glimepiride, vildagliptin, and dapagliflozin reduced blood glucose from 31.54 to 19.02 mmol/L, 30.24 to 17.20 mmol/L, 31.50 to 19.70 mmol/L, and 30.37 to 17.60 mmol/L, respectively, their corresponding lead complexes resulted in substantially weaker glycemic control after 14 days. Serum creatinine and uric acid levels were consistently elevated in mice treated with the lead-associated drug complexes compared with the parent drugs, indicating renal dysfunction and systemic toxicity. Histopathological findings further supported the presence of hepatic and nephrotoxic alterations following treatment with the lead-complex forms.
Conclusion: This study demonstrates that lead contamination can substantially alter the therapeutic behavior and toxicological profile of antidiabetic drugs through complex formation. These findings have broader relevance to environmentally exposed and microbiologically active systems, where pharmaceutical compounds and heavy metals may coexist and interact. The results highlight the need to further investigate heavy metal–drug interactions as an important but often overlooked factor in applied microbiology, environmental health, and biological risk assessment.
Keywords: Lead contamination; Antidiabetic drugs; Heavy metal complexation; Applied microbiology; Environmental toxicity; Creatinine; Uric acid; Biological risk
References
Afridi HI, Kazi TG, Kazi N, Jamali MK, Arain MB, Jalbani N, Baig JA, Sarfraz RA. Evaluation of status of toxic metals in biological samples of diabetes mellitus patients. Diabetes Research and Clinical Practice. 2008;80:280–288. https://doi.org/10.1016/j.diabres.2007.12.021. PMID: 18276029.
Ahren B, Schweizer A, Dejager S, Villhauer EB, Dunning BE, Foley JE. Mechanisms of action of the dipeptidyl peptidase-4 inhibitor vildagliptin in humans. Diabetes, Obesity and Metabolism. 2011;13:775–783. https://doi.org/10.1111/j.1463-1326.2011.01414.x. PMID: 21507182.
Barham D, Trinder P. An improved colour reagent for the determination of blood glucose by the oxidase system. Analyst. 1972;97:142–145. https://doi.org/10.1039/AN9729700142. PMID: 5037807.
Bener A, Obineche E, Gillett M, Pasha MA, Bishawi B. Association between blood levels of lead, blood pressure and risk of diabetes and heart disease in workers. International Archives of Occupational and Environmental Health. 2001;74:375–378. https://doi.org/10.1007/s004200100231. PMID: 11516073.
Bokara KK, Blaylock I, Denise SB, Bettaiya R, Rajanna S, Yallapragada PR. Influence of lead acetate on glutathione and its related enzymes in different regions of rat brain. Journal of Applied Toxicology. 2009;29:452–458. https://doi.org/10.1002/jat.1423. PMID: 19263481.
Brunton LL, Lazo JS, Parker KL, editors. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York, NY: McGraw-Hill; 2006. p. 1634–1638.
Cave M, Appana S, Patel M, Falkner KC, McClain CJ, Brock G. Polychlorinated biphenyls, lead, and mercury are associated with liver disease in American adults. Environmental Health Perspectives. 2010;118:1735–1742. https://doi.org/10.1289/ehp.1002720. PMID: 21126940; PMCID: PMC3002193.
Chen CJ, Wang SL, Chiou JM, Tseng CH, Chiou HY, Hsueh YM, Chen SY, Wu MM, Lai MS. Arsenic and diabetes and hypertension in human populations: a review. Toxicology and Applied Pharmacology. 2007;222:298–304. https://doi.org/10.1016/j.taap.2006.12.032. PMID: 17307211.
Chen YW, Yang CY, Huang CF, Hung DZ, Leung YM, Liu SH. Heavy metals, islet function and diabetes development. Islets. 2009;1:169–176. https://doi.org/10.4161/isl.1.3.9262. PMID: 21099269.
Coban TA, Senturk M, Ciftci M, Kufrevioglu OI. Effects of some metal ions on human erythrocyte glutathione reductase: an in vitro study. Protein and Peptide Letters. 2007;14:1027–1030. https://doi.org/10.2174/092986607782541060. PMID: 18221002.
Fossati P, Prencipe L, Berti G. Use of 3,5-dichloro-2-hydroxybenzenesulfonic acid/4-aminophenazone chromogenic system in direct enzymic assay of uric acid in serum and urine. Clinical Chemistry. 1980;26:227–231. https://doi.org/10.1093/clinchem/26.2.227. PMID: 7353268.
Heinegård D, Tiderström G. Determination of serum creatinine by a direct colorimetric method. Clinica Chimica Acta. 1973;43:305–310. https://doi.org/10.1016/0009-8981(73)90466-X.
Hunaiti AA, Soud M. Effect of lead concentration on the level of glutathione, glutathione S-transferase, reductase and peroxidase in human blood. Science of the Total Environment. 2000;248:45–50. https://doi.org/10.1016/S0048-9697(99)00548-3.
Kolachi NF, Kazi TG, Afridi HI, Kazi N, Khan S, Kandhro GA, Shah AQ, Baig JA, Wadhwa SK, Shah F, Jamali MK, Arain MB. Status of toxic metals in biological samples of diabetic mothers and their neonates. Biological Trace Element Research. 2011;143:196–212. https://doi.org/10.1007/s12011-010-8879-7. PMID: 20963639.
Larsen K. Creatinine assay by a reaction-kinetic principle. Clinica Chimica Acta. 1972;41:209–217. https://doi.org/10.1016/0009-8981(72)90513-X.
Lee DH, Lim JS, Song K, Boo Y, Jacobs DR Jr. Graded associations of blood lead and urinary cadmium concentrations with oxidative stress-related markers in the U.S. population: results from the Third National Health and Nutrition Examination Survey. Environmental Health Perspectives. 2006;114:350–354. https://doi.org/10.1289/ehp.8518. PMID: 16507456; PMCID: PMC1392227.
Leff T, Stemmer P, Tyrrell J, Jog R. Review on diabetes and exposure to environmental lead (Pb). Toxics. 2018;6:53–66. https://doi.org/10.3390/toxics6030054. PMID: 30200608; PMCID: PMC6161143.
Moon SS. Association of lead, mercury and cadmium with diabetes in the Korean population: The Korea National Health and Nutrition Examination Survey (KNHANES) 2009–2010. Diabetic Medicine. 2013;30:e143–e148. https://doi.org/10.1111/dme.12103. PMID: 23278294.
Padilla MA, Elobeid M, Ruden DM, Allison DB. An examination of the association of selected toxic metals with total and central obesity indices. International Journal of Environmental Research and Public Health. 2010;7:3332–3347. https://doi.org/10.3390/ijerph7093332. PMID: 20948927; PMCID: PMC2954548.
Plosker GL. Dapagliflozin: a review of its use in type 2 diabetes mellitus. Drugs. 2012;72:2289–2312. https://doi.org/10.2165/11209910-000000000-00000. PMID: 23170914.
Ris MD, Dietrich KN, Succop PA, Berger OG, Bornschein RL. Early exposure to lead and neuropsychological outcome in adolescence. Journal of the International Neuropsychological Society. 2004;10:261–270. https://doi.org/10.1017/S1355617704102154. PMID: 15012846.
Searle AK, Baghurst PA, van Hooff M, Sawyer MG, Sim MR, Galletly C, Clark LS, McFarlane AC. Tracing the long-term legacy of childhood lead exposure: a review of three decades of the Port Pirie Cohort Study. Neurotoxicology. 2014;43:46–56. https://doi.org/10.1016/j.neuro.2014.04.004. PMID: 24785378.
Surkan PJ, Zhang A, Trachtenberg F, Daniel DB, McKinlay S, Bellinger DC. Neuropsychological function in children with blood lead levels <10 μg/dL. Neurotoxicology. 2007;28:1170–1177. https://doi.org/10.1016/j.neuro.2007.07.007. PMID: 17868887; PMCID: PMC2276844.
Tsaih SW, Korrick S, Schwartz J. Lead, diabetes, hypertension, and renal function: the Normative Aging Study. Environmental Health Perspectives. 2004;112:1178–1182. https://doi.org/10.1289/ehp.7024. PMID: 15289163; PMCID: PMC1247478.
Zhai H, Chen C, Wang N, Chen Y, Nie X, Han B, Li Q, Xia F, Lu Y. Blood lead level is associated with non-alcoholic fatty liver disease in the Yangtze River Delta region of China in the context of rapid urbanization. Environmental Health. 2017;16:93–100. https://doi.org/10.1186/s12940-017-0304-7. PMID: 28859656; PMCID: PMC5580229.
View Dimensions
View Altmetric
Save
Citation
View
Share