Indomethacin,Curcumin,Acemetacin,Bioavailability,Damage,Gastrointestinal,Side effect,Drugs, Chinese herbal," /> Indomethacin,Curcumin,Acemetacin,Bioavailability,Damage,Gastrointestinal,Side effect,Drugs, Chinese herbal,"/> Evidence against the participation of a pharmacokinetic interaction in the protective effect of single-dose curcumin against gastrointestinal damage induced by indomethacin in rats
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Journal of Integrative Medicine ›› 2017, Vol. 15 ›› Issue (2): 151-157.doi: 10.1016/S2095-4964(17)60324-8

• Research Article • Previous Articles     Next Articles

Evidence against the participation of a pharmacokinetic interaction in the protective effect of single-dose curcumin against gastrointestinal damage induced by indomethacin in rats

Liliana Zazueta-Beltrána, Lorena Medina-Aymericha, Nadia Estela Díaz-Tristea, Aracely Evangelina Chávez-Piñab, Gilberto Castañeda-Hernándeza, Leticia Cruz-Antonioc   

  1. a Department of Pharmacology, Center for Research and Advanced Studies of the National Polytechnic Institute, 07360 Mexico City, Mexico 
    b Laboratory of Pharmacology, Institutional Program in Molecular Biomedicine, National School of Medicine and Homeopathy of the National Polytechnic Institute, Academic Area of Medicine of the Institute of Health Sciences, 07320 Mexico City, Mexico 
    c Superior Studies Faculty of Zaragoza, Universidad National Autonomous of Mexico, 09230 Mexico City,Mexico
  • Received:2016-09-09 Accepted:2016-12-06 Online:2017-03-15 Published:2017-03-15
  • Contact: Leticia Cruz-Antonio, PhD; E-mail:


To determine the role of a pharmacokinetic interaction in the protective effect of curcumin against the gastric damage induced by indomethacin administration as such or as its prodrug acemetacin.


Wistar rats orally received single dose of indomethacin (30 mg/kg) with and without curcumin (30 mg/kg); gastric injury was evaluated by determining the total damaged area. Additional groups of rats received an oral single dose of indomethacin (30 mg/kg) or its prodrug acemetacin (34.86 mg/kg) in the presence or absence of curcumin (30 mg/kg). Indomethacin and acemetacin concentrations in plasma from blood draws were determined by high-performance liquid chromatography. Plasma concentration-against-time curves were constructed, and bioavailability parameters, maximal concentration (Cmax) and area under the curve to the last sampling time (AUC0-t) were estimated.


Concomitant administration of indomethacin and curcumin resulted in a significantly reduced gastric damage compared to indomethacin alone. However, co-administration of curcumin did not produce any significant alteration in the bioavailability parameters of indomethacin and acemetacin after administration of either the active compound or the prodrug.


Curcumin exhibits a protective effect against indomethacin-induced gastric damage, but does not produce a reduction of the bioavailability of this nonsteroidal anti-inflammatory drug, indomethacin. Data thus suggest that a pharmacokinetic mechanism of action is not involved in curcumin gastroprotection.

Key words: Indomethacin, Curcumin, Acemetacin, Bioavailability, Damage, Gastrointestinal, Side effect, Drugs, Chinese herbal

1 Goldstein JY, Cryer B.Gastrointestinal injury associated with NSAID use: a case study and review of risk factors and preventative strategies. Drug Healthc Patient Saf.2015; 7: 31-41.
2 Scheiman JM.NSAID-induced gastrointestinal injury: a focused update for clinicians. J Clin Gastroenterol.2016; 50(1): 5-10.
3 Yeomans N, Wilson I, Långström G, Hawkey C, Naesdal J, Walan A, Wiklund I.Quality of life in chronic NSAID users: a comparison of the effect of omeprazole and misoprostol. Scand J Rheumatol.2001; 30(6): 328-334.
4 Wallace JL, Syer S, Denou E, de Palma G, Vong L, McKnight W, Jury J, Bolla M, Bercik P, Collins SM, Verdu E, Ongini E. Proton pump inhibitors exacerbate NSAIDinduced small intestinal injury by inducing dysbiosis.Gastroenterology. 2011; 141(4): 1314-1322.
5 Falcão HS, Mariath IR, Diniz MF, Batista LM, Barbosa- Filho JM.Plants of the American continent with antiulcer activity. Phytomedicine.2008; 15(1-2): 132-146.
6 Hussain L, Akash MS, Naseem S, Rehman K, Ahmed KZ.Anti-ulcerogenic effects of Salmalia malabarica in gastric ulceration—pilot study. Adv Clin Exp Med. 2015; 24(4): 595-605.
7 Navarrete A, Oliva I, Sánchez-Mendoza ME, Arrieta J, Cruz-Antonio L, Castañeda-Hernández G.Gastroprotection and effect of the simultaneous administration of Cuachalalate(Amphipterygium adstringens) on the pharmacokinetics and anti-inflammatory activity of diclofenac in rats. J Pharm Pharmacol.2005; 57(12): 1629-1636.
8 Chattopadhyay I, Bandyopadhyay U, Biswas K, Maity P, Banerjee RK.Indomethacin inactivates gastric peroxidase to induce reactive-oxygen-mediated gastric mucosal injury and curcumin protects it by preventing peroxidase inactivation and scavenging reactive oxygen. Fre Radic Biol Med. 2006; 40(8): 1397-1408.
9 Menozzi A, Pozzoli C, Poli E, Martelli M, Martelli L, Zullian C, Bertini S.Effects of oral curcumin on indomethacin-induced small intestine damage in the rat. Drug Discov Ther.2009; 3(2): 71-76.
10 Morsy MA, El-Moselhy MA.Mechanisms of the protective effects of curcumin against indomethacin-induced gastric ulcer in rats. Pharmacology.2013; 91(5-6): 267-274.
11 Díaz-Triste NE, González-García MP, Jiménez- Andrade JM, Castañeda-Hernández G, Chávez-Piña AE.Pharmacological evidence for the participation of NOcGMP- KATP pathway in the gastric protective effect of curcumin against indomethacin-induced gastric injury in the rat. Eur J Pharmacol.2014; 730: 102-106.
12 Chávez-Piña AE, McKnight W, Dicay M, Castañeda- Hernández G, Wallace JL. Mechanisms underlying the antiinfl ammatory activity and gastric safety of acemetacin.Br J Pharmacol. 2007; 152(6): 930-938.
13 Shehata TM, Abdallah MH, Ibrahim MM.Proniosomal oral tablets for controlled delivery and enhanced pharmacokinetic properties of acemetacin. AAPS Pharm Sci Tech.2015; 16(2): 375-383.
14 Rechziegler H, Zündorf P.Acemetacin in the treatment of rheumatic diseases: an open, multi-centre trial. Curr Med Res Opinion.1985; 9(10): 701-707.
15 Sakunthala Devi PR, Reddy AG, Rao GS, Kumar CS, Boobalan G.Pharmacokinetic interaction of curcumin and glibenclamide in diabetic rats. Vet World.2015; 8(4): 508-511.
16 Purwar B, Shrivastava A, Arora N, Kumar A, Saxena Y.Effects of curcumin on the gastric emptying of albino rats. Indian J Physiol Pharmacol.2012; 56(2): 168-173.
17 Zhang W, Tan TM, Lim LY.Impact of curcumin-induced changes in P-glycoprotein and CYP3A expression on the pharmacokinetics of peroral celiprolol and midazolam in rats. Drug Metab Dispos.2007; 35(1): 110-115.
18 Ortiz MI, González-García MP, Ponce-Monter HA, Castañeda-Hernández G, Aguilar-Robles P.Synergistic effect of the interaction between naproxen and citral on infl ammation in rats.Phytomedicine. 2010; 18(1): 74-79.
19 Chávez-Piña AE, Favari L, Castañeda-Hernández G.Pharmacokinetics of acemetacin and its active metabolite indomethacin in rats during acute hepatic damage and liver regeneration. Ann Hepatol.2009; 8(2): 141-147.
20 Chávez-Piña AE, Tapia-Álvarez GR, Reyes-Ramínrez A, Navarrete A. Carbenoxolone gastroprotective mechanism: participation of nitric oxide/(c) GMP/K(ATP) pathway in ethanol-induced gastric injury in the rat.Fundam Clin Pharmacol. 2011; 25(6): 717-722.
21 Ismail HAF, Khalifa MM, Hassan MK, Ashour OM.Investigating the mechanisms underlying the gastroprotective effect of nocorandil. Pharmacology.2007; 79(2): 76-85.
22 Medeiros JVR, Gadelha GG, Lima SJ, Garcia JA, Soares PM, Santos AA, Brito GA, Ribeiro RA, Souza MH.Role of the NO/cGMP/KATP pathway in the protective effects of sildenafi l against ethanol-induced gastric damage in rats. Br J Pharmacol.2008; 153(4): 721-727.
23 23 Santana AP, Tavares BM, Lucetti LT, Gouveia FS Jr, Ribeiro RA, Soares PM, Sousa EH, Lopes LG, Medeiros JV, Souza MH. The nitric oxide donor cis-[Ru(bpy)2(SO3)NO](PF6) increases gastric protection in mice—involvement of the soluble guanylate/KATP pathway.Nitric Oxide. 2015; 45: 35-42.
24 Silva RO, Lucetti LT, Wong DV, Aragão KS, Junior EM, Soares PM, Barbosa AL, Ribeiro RA, Souza MH, Medeiros JV.Alendronate induces gastric damage by reducing nitric oxide synthase expression and NO/cGMP/KATP signalling pathway. Nitric Oxide.2014; 40: 22-30.
25 De Paz-Campos MA, Chávez-Piña AE, Ortiz MI, Castañeda-Hernández G. Evidence for the participation of ATP-sensitive potassium channels in the antinociceptive effect of curcumin.Korean J Pain. 2012; 25(4): 221-227.
26 Pulido-Morán M, Moreno-Fernandez J, Ramirez-Tortosa C, Ramirez-Tortosa M.Curcumin and health. Molecules.2016; 21: 264.
27 Kusuhara H, Furuie H, Inano A, Sunagawa A, Yamada S, Wu C, Fukizawa S, Morimoto N, Ieiri I, Morishita M, Sumita K, Mayahara H, Fujita T, Maeda K, Sugiyama Y.Pharmacokinetic interaction study of sulphasalazine in healthy subjects and the impact of curcumin as an in vivo inhibitor of BCRP. Br J Pharmacol.2012; 166(6): 1793-1803.
28 Kim SB, Cho SS, Cho HJ, Yoon IS.Modulation of hepatic cytochrome P450 enzymes by curcumin and its pharmacokinetic consequences in Sprague-Dawley rats.Pharmacogn Mag. 2015; 11(Suppl 4): S480-S584.
29 Volak LP, Hanley MJ, Masse G, Hazarika S, Harmatz JS, Badmaev V, Majeed M, Greenblatt DJ, Court MH.Effect of a herbal extract containing curcumin and piperine on midazolam, fl urbiprofen and paracetamol (acetaminophaen) pharmacokinetics in healthy voluteers. Br J Clin Pharmacol.2012; 75(2): 450-462.
30 Kumar A, Purwar B, Shrivastava A, Pandey S.Effects of curcumin on the intestinal motility of albino rats.Indian J Physiol Pharmacol. 2010; 54(3): 284-288.
31 Maurer HH, Tauvel FX, Kraemer T.Screening procedure for detection of non-steroidal anti-infl ammatroy drugs and their metabolites in urine as part of a systematic toxicological analysis procedure for acidic drugs and poisons by gas chromatography-mass spectrometry after extractive methylation. J Anal Toxicol.2001; 25(4): 237-244.
32 Parsons RL, Kaye CM, Raymond K.Pharmacokinetics of salycilate and indomethacin in celiac disease. Europ J Clin Pharmacol.1977; 11(6): 473-477.
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