Linagliptin is an antidiabetic drug used for the treatment of type-2 diabetes. The oral bioavailability of linagliptin is low (29.5%) due to its first pass metabolism in the intestine and liver. Gallic acid and ellagic acid are natural polyphenols which are widely distributed in fruits and medicinal plants. Gallic acid and ellagic acid have been reported to inhibit p-glycoprotein (p-gp) and enhance the bioavailability of p-gp substrate drugs. Hence, the purpose of the study was to evaluate the effect of gallic acid and ellagic acid on intestinal transport and bioavailability of linagliptin, a p-gp substrate in diabetic rats.
The intestinal transport of linagliptin was assessed by conducting an in situ single-pass intestinal perfusion study. The oral pharmacokinetics was evaluated by conducting oral bioavailability study in diabetic rats.
After pretreatment with gallic acid and ellagic acid, no significant change in effective permeability of linagliptin was observed at the ileum part of the rat intestine. A significant improvement in the peak serum concentration (Cmax) and area under the serum concentration time profile (AUC), AUMC, AUCtotal and decrease in clearance were observed in rats pretreated with gallic acid and ellagic acid.
This study demonstrates that gallic acid and ellagic acids increase the bioavailability of oral linagliptin in rats due to the inhibition of p-gp. These animal data need to be confirmed in a clinical setting to determine whether linagliptin dosing should be adjusted when given concomitantly with these phytochemicals or gallic acid/ellagic acid-containing dietary supplements.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
 Deacon CF, Holst JJ. Linagliptin a xanthine based di-peptidyl peptidase-4 inhibitor with an unusual profile for the treatment of type-2 diabetes. Expert Opin Investig Drugs 2011;19:133–40.10.1517/13543780903463862Search in Google Scholar PubMed
 Forst T, Uhlig-Laske B, Ring A, Ritzhaupt A, Graefe-mody U, Dugi KA. The oral DPP-4 inhibitor linagliptin significantly lowers HbA1c after 4 weeks of treatment in patients with type-2 diabetes mellitus. Diabetes Obes Metab 2011;13:542–50.10.1111/j.1463-1326.2011.01386.xSearch in Google Scholar PubMed
 Retlich S, Duval V, Ring A. Pharmacokinetics and pharmacodynamics of single intravenous doses (0.5–10 mg) and determination of absolute bioavailability of the dipeptidyl peptidase-4 inhibitor linagliptin (B1 1356) in healthy male subjects. Clin Pharmacokinet 2010;49:829–40.10.2165/11536620-000000000-00000Search in Google Scholar PubMed
 Fuchs H, Runge F, Held HD. Excretion of the dipeptidyl peptidase-4 inhibitor linagliptin in rats is primarily by biliary excretion and P-glycoprotein mediated efflux. Eur J Pharm Sci 2012;45:533–8.10.1016/j.ejps.2011.11.018Search in Google Scholar PubMed
 Battestin V, Matsuda LK, Macedo GA. Fontesaplicacaoes de taninos tanasesemalimentos. Alim Nutrients Araraquara 2004;15:63–72.Search in Google Scholar
 Chia Y, Rajbanshi R, Calhoun C, Chin RH. Anti-neoplastic effects of gallic acid, a major component of toonasinensis leaf extract, on oral squamous carcinoma cells. Molecules 2010;15:8377–89.10.3390/molecules15118377Search in Google Scholar PubMed PubMed Central
 Amin MM, Arbid MS. Estimation of ellagic acid and repaglinide effects on insulin signaling, oxidative stress and inflammatory mediators of liver, pancreas, adipose tissue and brain in insulin resistant type 2 diabetic rats. Appl Physiol Nutr Metab 2017;42:181–92.10.1139/apnm-2016-0429Search in Google Scholar PubMed
 Mali VR, Bodhankar SL, Mohan V, Thakurdesai PA. Subacute toxicity of ellagic acid in cholesterol fed hyperlipidemic rats. Toxicol Int 2008;15:91–5.Search in Google Scholar
 Landete JM. Ellagitannins, ellagic acid and their derived metabolites: a review about source, metabolism, functions and health. Food Res Int 2011;44:1150–60.10.1016/j.foodres.2011.04.027Search in Google Scholar
 Athukuri BL, Neerati P. Enhanced oral bioavailability of diltiazem by the influence of gallic acid and ellagic acid in male Wistar rats. Involvement of CYP3A4 and P-glycoprotein inhibition. Phytother Res 2017;31:1441–8.10.1002/ptr.5873Search in Google Scholar PubMed
 Satish KB, Ramgopal A, Praveen K. Capsaicin pretreatment enhanced the bioavailability of fexofenadine in rats by P-glycoprotein modulation: in vitro, in situ and in vivo evaluation. Drug Dev Ind Pharm 2017;43:932–8.10.1080/03639045.2017.1285310Search in Google Scholar PubMed
 Venkateshwaran S, Pari L. Antioxidant effect of Phaseolus vulgaris in streptozotocin induced diabetic rats. Asian Pac J Clin Nutr 2002;11:206–9.10.1046/j.1440-6047.2002.00292.xSearch in Google Scholar
 Athukuri BL, Neerati P. Enhanced oral bioavailability of metoprolol with gallic acid and ellagic acid in male Wistar rats: involvement of CYP2D6 inhibition. Drug Metab Pers Ther 2016;31:229–34.10.1515/dmpt-2016-0029Search in Google Scholar PubMed
 Sutton SC, Rinaldi MT, Vukovinsky KE. Comparison of the gravimetric, phenol red, and 14C-PEG-3350 methods to determine water absorption in the rat single pass intestinal perfusion model. AAPS Pharm Sci 2001;3:E25.10.1208/ps030325Search in Google Scholar
 Bedada SK, Yellu NR, Neerati P. Effect of resveratrol on the pharmacokinetics of fexofenadine in rats. Involvement of P-glycoprotein inhibition. Pharmacol Res 2016;68:338–43.10.1016/j.pharep.2015.08.018Search in Google Scholar
 Stephens RH, O’Neill CA, Warhurst A, Carlson GL, Rowland M, Warhurst G. Kinetic profiling of P-glycoprotein-mediated drug efflux in rat and human intestinal epithelia. J Pharmacol Exp Ther 2001;296:584–91.Search in Google Scholar PubMed
 Hoimark L, Laursen T, Rungby J. Potential role of linagliptin as an oral once-daily treatment for patients with type 2 diabetes. Diabetes Metab Syndr Obes 2012;5:295–302.10.2147/DMSO.S16288Search in Google Scholar PubMed
 Yan Z, Colbin B, Donald WM. In vitro and in vivo models for assessing drug efflux transport activity. Adv Drug Deliv Rev 2003;55:31–51.10.1016/S0169-409X(02)00170-9Search in Google Scholar PubMed
© 2019 Walter de Gruyter GmbH, Berlin/Boston