Preclinical Study to Evaluate the Effect of Polyherbal Formulation on Metformin: Potential Herb-drug Interaction

Author(s): Devendra Kumar*, Neerja Trivedi, Rakesh Kumar Dixit

Journal Name: The Natural Products Journal

Volume 9 , Issue 1 , 2019

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Graphical Abstract:


Objective: The aim of the present study was to examine the effect of a polyherbal formulation (PHF) on pharmacokinetics and pharmacodynamics of metformin in rats.

Methods: The present study was conducted to determine the beneficial outcomes of PHF along with metformin by studying herb-drug interactions. PHF was prepared by five indigenous herbs, Those are being used traditionally as antidiabetic in India. PHF doses (100 mg/kg/day) were administered to Sprague-Dawley rats by an oral route of different groups for multiple weeks except for control. Metformin (100 mg/kg) was orally administered at 7th and 30th day to control and PHF pretreated rats for pharmacokinetics study while pharmacodynamics study was conducted in PHF treated and untreated diabetic rats. No more significant difference was found in the pharmacokinetic parameters in PHF treated at 7th day while a significant increase was found in AUC at the 30th day.

Results: The hypoglycemic effect was observed with a combination of metformin and PHF, significantly more compared to control. Metformin decreased the blood glucose 1.51 fold at 7th day and 1.7 fold at 30th day respectively, compared to control.

Conclusion: Thus, this finding indicates that PHF increased the AUC of metformin. It might increase bioavailability through drug-herb interaction thereby affecting the therapeutic effect. This formulation can be considered as an adjunct to metformin in the management of diabetes mellitus.

Keywords: Metformin, pharmacokinetics, pharmacodynamic, PHF, diabetes, hypoglycemic.

American Diabetes Association. Standards of medical care in diabetes-2009. Diabetes Care, 2009, 32(Suppl. 1), S13-S61.
Scheen, A.J. Clinical pharmacokinetics of metformin. Clin. Pharmacokinet., 1996, 30(5), 359-371.
Sirtori, C.R.; Franceschini, G.; Galli-Kienle, M.; Cighetti, G.; Galli, G.; Bondioli, A. Disposition of metformin (N,N-dimethylbigu-anide) in man. Clin. Pharmacol. Ther., 1978, 24(6), 683-693.
Pentikainen, P.J.; Neuvonen, P.J.; Penttila, A. Pharmacokinetics of metformin after intravenous and oral administration to man. Eur. J. Clin. Pharmacol., 1979, 16(3), 195-202.
Tucker, G.T.; Casey, C.; Phillips, P.J.; Connor, H.; Ward, J.D.; Woods, H.F. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br. J. Clin. Pharmacol., 1981, 12(2), 235-246.
Grover, J.K.; Vats, V.; Rathi, S.S. Anti-hyperglycemic effect of Eugenia jambolana and Tinospora cordifolia in experimental diabetes and their effects on key metabolic enzymes involved in carbohydrate metabolism. J. Ethnopharmacol., 2000, 73(3), 461-470.
Kumar, R.; Balaji, S.; Uma, T.S.; Sehgal, P.K. Fruit extracts of Momordica charantia potentiate glucose uptake and up-regulate Glut-4, PPAR gamma and PI3K. J. Ethnopharmacol., 2009, 126(3), 533-537.
Oh, W.K.; Lee, C.H.; Lee, M.S.; Bae, E.Y.; Sohn, C.B.; Oh, H. Antidiabetic effects of extracts from Psidium guajava. J. Ethnopharmacol., 2005, 96(3), 411-415.
Roman-Ramos, R.; Flores-Saenz, J.L.; Alarcon-Aguilar, F.J. Anti-hyperglycemic effect of some edible plants. J. Ethnopharmacol., 1995, 48(1), 25-32.
Vats, V.; Yadav, S.P.; Grover, J.K. Ethanolic extract of Ocimum sanctum leaves partially attenuates streptozotocin-induced alterations in glycogen content and carbohydrate metabolism in rats. J. Ethnopharmacol., 2004, 90(1), 155-160.
Kumar, D.; Trivedi, N.; Dixit, R.K. Evaluation of the synergistic effect of Allium sativum, Eugenia jambolana, Momordica charantia, Ocimum sanctum and Psidium guajav on hepatic and intestinal drug metabolizing enzymes in rats. J. Intercult. Ethnopharmacol., 2016, 5(4)
Bhatta, R.S.; Kumar, D.; Chhonker, Y.S.; Saxena, A.K.; Jain, G.K. Bioanalytical method development and validation of novel antithrombotic agent S002-333 by LC-MS/MS and its application to pharmacokinetic studies. BMC, 2010, 24(11), 1234-1239.
Kumar, D.; Khanna, A.K.; Pratap, R.; Sexana, J.K.; Bhatta, R.S. Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone. Indian J. Pharmacol., 2012, 44(1), 57-62.
Bhatta, R.S.; Rathi, C.; Chandasana, H.; Kumar, D.; Chhonker, Y.S.; Jain, G.K. LC–MS method for determination of amphotericin B in rabbit tears and its application to ocular pharmacokinetic study. Chroma, 2011, 73(5-6), 487-493.
Bhatta, R.S.; Chandasana, H.; Rathi, C.; Kumar, D.; Chhonker, Y.S.; Jain, G.K. Bioanalytical method development and validation of natamycin in rabbit tears and its application to ocular pharmacokinetic studies. J. Pharm. Biomed. Anal., 2011, 54(5), 1096-1100.
Park, J.M.; Moon, C.H.; Lee, M.G. Pharmacokinetic changes of methotrexate after intravenous administration to streptozotocin-induced diabetes mellitus rats. Res. Commun. Mol. Pathol. Pharmacol., 1996, 93(3), 343-352.
Kim, Y.C.; Lee, A.K.; Lee, J.H.; Lee, I.; Lee, D.C.; Kim, S.H. Pharmacokinetics of theophylline in diabetes mellitus rats: Induction of CYP1A2 and CYP2E1 on 1,3-dimethyluric acid formation. Eur. J. Pharm. Sci., 2005, 26(1), 114-123.
Bailey, C.J.; Day, C. Metformin: Its botanical background. Prac. Diab. Int, 2004, 21(3), 115-117.
Hu, Z.; Yang, X.; Ho, P.C.; Chan, S.Y.; Heng, P.W.; Chan, E. Herb-drug interactions: A literature review. Drugs, 2005, 65(9), 1239-1282.
Singh, R.; Panduri, J.; Kumar, D.; Kumar, D.; Chandsana, H.; Ramakrishna, R. Evaluation of memory enhancing clinically available standardized extract of Bacopa monniera on P-glycoprotein and cytochrome P450 3A in Sprague-Dawley rats. PLoS One, 2013, 8(8), e72517.
Gohil, K.; Patel, J.A. Herb-drug interactions: A review and study based on assessment of clinical case reports in literature. Ind. J. Pharmacol., 2007, 39(3), 129.
Kumar, D.; Trivedi, N.; Dixit, R.K. Evaluation of the potential effect of Allium sativum, Momordica charantia, Eugenia jambolana, Ocimum sanctum, and Psidium guajava on intestinal p-glycoprotein in rats. J. Intercult. Ethnopharmacol., 2017, 6(1), 68-74.
Shimojo, N.; Ishizaki, T.; Imaoka, S.; Funae, Y.; Fuji, S.; Okuda, K. Changes in amounts of cytochrome P450 isozymes and levels of catalytic activities in hepatic and renal microsomes of rats with streptozocin-induced diabetes. Biochem. Pharmacol., 1993, 46(4), 621-627.
Sakuma, T.; Honma, R.; Maguchi, S.; Tamaki, H.; Nemoto, N. Different expression of hepatic and renal cytochrome P450s between the streptozotocin-induced diabetic mouse and rat. Xenobiotica, 2001, 31(4), 223-237.
Choi, Y.H.; Lee, M.G. Effects of enzyme inducers and inhibitors on the pharmacokinetics of metformin in rats: Involvement of CYP2C11, 2D1 and 3A1/2 for the metabolism of metformin. Br. J. Pharmacol., 2006, 149(4), 424-430.
Kimura, N.; Masuda, S.; Tanihara, Y.; Ueo, H.; Okuda, M.; Katsura, T. Metformin is a superior substrate for renal organic cation transporter OCT2 rather than hepatic OCT1. Drug Metab. Pharmacokinet., 2005, 20(5), 379-386.
Terada, T.; Masuda, S.; Asaka, J.; 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), 1696-1701.
Proctor, W.R.; Bourdet, D.L.; Thakker, D.R. Mechanisms underlying saturable intestinal absorption of metformin. Drug Metab. Dispos., 2008, 36(8), 1650-1658.
Wang, D.S.; Jonker, J.W.; Kato, Y.; Kusuhara, H.; Schinkel, A.H.; Sugiyama, Y. Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J. Pharmacol. Experiment. Therapeut, 2002, 302(2), 510-515.
Muller, J.; Lips, K.S.; Metzner, L.; Neubert, R.H.; Koepsell, H.; Brandsch, M. Drug specificity and intestinal membrane localization of human Organic Cation Transporters (OCT). Biochem. Pharmacol., 2005, 70(12), 1851-1860.
Seithel, A.; Karlsson, J.; Hilgendorf, C.; Bjorquist, A.; Ungell, A.L. Variability in mRNA expression of ABC- and SLC-transporters in human intestinal cells: Comparison between human segments and Caco-2 cells. Eur. J. Pharm. Sci., 2006, 28(4), 291-299.
Masuda, S.; Terada, T.; Yonezawa, A.; Tanihara, Y.; Kishimoto, K.; Katsura, T. Identification and functional characterization of a new human kidney-specific H+/organic cation antiporter, kidney-specific multidrug and toxin extrusion 2. J. Am. Soc. Nephrol., 2006, 17(8), 2127-2135.
Zhou, M.; Xia, L.; Wang, J. Metformin transport by a newly cloned proton-stimulated organic cation transporter (plasma membrane monoamine transporter) expressed in human intestine. Drug Metab. Dispos., 2007, 35(10), 1956-1962.

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Article Details

Year: 2019
Page: [69 - 76]
Pages: 8
DOI: 10.2174/2210315508666180507152031
Price: $25

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