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Anti-inflammatory activity of anti-hyperlipidemic drug, fenofibrate, and its phase-I metabolite fenofibric acid: in silico, in vitro, and in vivo studies

Abstract

Fenofibrate, an anti-hyperlipidemic drug and its phase-I biotransformed metabolite fenofibric acid, was studied for COX-1 (PDB ID: 3N8Y) and COX-2 (PDB ID: 1PXX) inhibition potentials in silico and in vitro for their effects on human recombinant COX-2 enzyme isolated from a Baculovirus expression system in sf21 cells (EC 1.14.99.1) using a conventional spectrophotometric assay. Furthermore, the compounds were also screened for their anti-inflammatory potentials in vivo using carrageenan-induced paw oedema method in Wistar rats. The test compounds fenofibric acid, fenofibrate, and the standard drug diclofenac exhibited binding energies of − 9.0, − 7.2, and − 8.0 kcal mol−1, respectively, against COX-2 and − 7.2, − 7.0, and − 6.5 kcal mol−1, respectively, against COX-1. In in vitro studies, both the test compounds inhibited COX-2 enzyme activity. Fenofibric acid showed an IC50 value of 48 nM followed by fenofibrate (82 nM), while diclofenac showed an IC50 value of 58 nM. Furthermore, under in vivo conditions in carrageenan-induced paw oedema rodent model, fenofibric acid exhibited relatively potent anti-inflammatory activity compared with fenofibrate. Hence, we conclude that fenofibric acid and fenofibrate are not only anti-hyperlipidemic but also shows potent anti-inflammatory activity, which may have an additional impact in the treatment of diabetic complications, viz., hyperlipidemia and inflammation leading to atherosclerosis.

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References

  1. Baker CS, Hall RJ, Evans TJ, Pomerance A, Maclouf J, Creminon C, Yacoub MH, Polak JM (1999) Cyclooxygenase-2 is widely expressed in Atherosclerotic lesions affecting native and transplanted human coronary arteries and colocalizes with inducible nitric oxide synthase and coronary arteries and colocalizes with inducible nitric oxide synthase and nitrotyrosine particularly in macrophages. Arterioscler Thromb Vasc Biol 19:646–655

    Article  PubMed  CAS  Google Scholar 

  2. Belton O, Fitzgerald D (2003) Cyclooxygenase-2 inhibitors and atherosclerosis. J Am Coll Cardiol 41:1820–1822

    Article  PubMed  Google Scholar 

  3. Boamponsem AG, Boamponsem LK (2011) The role of inflammation in atherosclerosis. Adv Appl Sci Res 2:194–207

    CAS  Google Scholar 

  4. Broncel M, Cieslak D, Koter MM, Duchnowicz P, Mackiewicz K, Chojnowska JJ (2006) The anti-inflammatory and antioxidants effects of micronized fenofibrate in patients with visceral obesity and dyslipidemia. Pol Merkur Lekarski 20:547–550

    PubMed  Google Scholar 

  5. Burleigh ME, Babaev VR, Oates BJ, Harris RC, Gautam S, Riendeau D, Marnett LJ, Marrow JD, Fazio S, Linton MF (2002) Cyclooxygenase-2 promotes early atherosclerotic lesion formation in LDL receptor-deficient mice. Circulation 105:1816–1823

    Article  PubMed  CAS  Google Scholar 

  6. Chakravarthi PV, Gopakumar N (2010) Anti-inflammatory activity of red and white lotus seeds (Nelumbo nucifera) in albino rats. Vet World 3:157–159

    Article  Google Scholar 

  7. Chen YJ, Quilley J (2008) Fenofibrate treatment of diabetic rats reduces nitrosative stress, renal cyclooxygenase-2 expression and enhanced renal prostaglandin release. J Pharmacol Exp Ther 324:658–663

    Article  PubMed  CAS  Google Scholar 

  8. Cipollone F, Fazia ML (2006) COX-2 and atherosclerosis. J Cardio Vasc Pharmacol 47:26–36

    Article  Google Scholar 

  9. Copeland RA, Williams JM, Giannaras J, Nurnberg S, Covington M, Pinto D, Pick S, Trzaskos JM (1994) Mechanism of selective inhibition of the inducible isoform or prostaglandin G/H synthase. Proc Natl Acad Sci USA 91:11202–11206

    Article  PubMed  CAS  Google Scholar 

  10. Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W (1996) The PPARalpha-leukotriene B4 pathway to inflammation control. Nature 384:39–43

    Article  PubMed  CAS  Google Scholar 

  11. Duggan KC, Hermanson DJ, Musee J, Prusakiewicz JJ, Scheib JL, Carter BD, Banerjee S, Oates JA, Marnett LJ (2011) (R)-profens are substrate selective inhibitors of endo cannabinoid oxygenation by COX-2. Nat Chem Biol 7:803–809

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Elhenawy AA, El-Gazzar MA, Mohammed HM (2014) Synthesis, anti-inflammatory, analgesic, molecular modelling and ADMET studies of Novel diclofenac derivatives containing alanyl moiety. CMR 6:69–77

    Google Scholar 

  13. Engelbertsen D, Fong T, Duner P, Kotova O, Soderberg I, Alm R, Gomez MF, Nilsson J, Bengtsson E (2012) Increased inflammation in atherosclerotic lesions of diabetic akita-LDLr mice compared to non-diabetic LDLr mice. Exp Diabetes Res. https://doi.org/10.1155/2012/176162

    PubMed  PubMed Central  Article  Google Scholar 

  14. Enns JE, Taylor CG, Zahradka P (2013) Diabetic cardiomyopathy in the role of inflammation in Type-2 diabetes-driven atherosclerosis. In: Taran B, Dhalla NS (eds) Diabetic cardiomyopathy. Springer, New York, pp 213–237

    Google Scholar 

  15. Faxon DP, Fuster V, Lippy P, Beckman JA, Hiatt WR, Thompson RW, American Heart Association et al (2004) Atherosclerosis vascular disease conference: writing group III: pathophysiology. Circulation 109:2617–2625

    Article  PubMed  Google Scholar 

  16. Frostegard J (2013) Immunity, atherosclerosis and cardiovascular disease. BMC Med 11:117

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Goto M (2010) A comparative study of anti-inflammatory and anti-dyslipidemic effects of fenofibrate and statins on rheumatoid arthritis. Mod Rheumatol 20:238–243

    Article  PubMed  CAS  Google Scholar 

  18. Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, Grobbee DE, Cass A, Chalmers J, Perkovic V (2010) Effects of fibrates on cardiovascular outcomes: a systemic review and meta-analysis. Lancet 375:1875–1888

    Article  PubMed  CAS  Google Scholar 

  19. Keating GM, Ormrod D (2002) Micronised fenofibrate. An update review of its clinical efficacy in the management of dyslipidemia. Drugs 62:1909–1944

    Article  PubMed  CAS  Google Scholar 

  20. Kleemann R, Verschuren L, de Rooij BJ, Linderman J, De Matt MM, Szalai AJ, Princen HMG, Kooistra T (2004) Evidence for anti-inflammatory activity of statins and PPAR activators in human C-reactive protein transgenic mice in vivo and in cultures human hepatocytes in vitro. Blood 103:4188–4194

    Article  PubMed  CAS  Google Scholar 

  21. Kumar NS, Sathiyamoorthy S, Ramya M, Yang DU, Lee HN, Yang DC (2012) Molecular docking studies of anti-apoptotic BCL-2, BCL-XL, and MCL-1 proteins with ginsenosides from Panax ginseng. J Enzyme Inhib Med Chem 27:685–692

    Article  CAS  Google Scholar 

  22. Lee JN, Dutta RK, Sg Kim, Lim JY, Kim SJ, Choe SK, Yoo KW, Song SR, Park DS, So HS, Park R (2013) Fenofibrate, a peroxisome proliferator-activated receptor a ligand, prevents abnormal liver functions induced by a fasting-refeeding process. Biochem Biophys Res Commun 442:22–27

    Article  PubMed  CAS  Google Scholar 

  23. Moallem SA, Imenshahidi M, Shahini N, Javan AR, Karimi M, Alibolandi M, Ghandadi M, Etemad L, Motamedshariaty V, Hosseini T, Hadizadeh F (2013) Synthesis, anti-inflamatory and antinociceptive activities and cytotoxic effect of novel thiazolidin-4-ones derivatives as selective cyclooxygenase inhibitors. Iran J Med Sci 16:1238–1244

    CAS  Google Scholar 

  24. Moscoso GA, Ruiz E, Carnero M, Reguillo F, Rodriguez E, Tejerina T, Redondo S (2013) Relationship between serum levels of triglycerides and vascular inflammation measured as COX-2 in arteries from diabetic patients: a translational study. Lipids Health Dis 12:1–9

    Article  CAS  Google Scholar 

  25. Oilveira ACP, Bertollo CM, Rocha LTS, Nascimento EB, Costa KA, Coelho MM (2007) Antinociceptive and antiedematogenic activities of fenofibrate, an agonist of PPAR alpha and pioglitazone, an agonist of PPAR gamma. Eur J Pharmacol 561:194–201

    Article  CAS  Google Scholar 

  26. Okopien B, Krysiak R, Herman ZS (2006) Herman effects of short-term fenofibrate treatment on circulating markers of inflammation and hemostasis in patients with impaired glucose tolerance. J Clin Endocrinol Metab 91:1770–1778

    Article  PubMed  CAS  Google Scholar 

  27. Pouplana R, Lozano JJ, Ruiz J (2002) Molecular modelling of the differential interaction between several non-steroidal anti-inflammatory drugs and human prostaglandin endoperoxide H synthase-2 (h-PGHS-2). J Mol Graph 20:329–343

    Article  CAS  Google Scholar 

  28. Prasad GS, Govardhan P, Girisham S, Reddy SM (2014) Fungal mediated generation of metabolites of fenofibrate and enhanced pharmacological activity of main metabolite fenofibric acid. Drug Metab Lett 8:88–95

    Article  PubMed  CAS  Google Scholar 

  29. Ravi J, Kiran G, Sarangapani M, Sriram R (2016) Synthesis, invivo anti-inflammatory activity and molecular docking studies of New Isatin derivatives. Int J Med Chem. https://doi.org/10.1155/2016/2181027

    Article  Google Scholar 

  30. Rowlinson SW, Kiefer JR, Prusakiewicz JJ, Pawlitz JL, Kozak KR, Kalgutkar AS, Stallings WC, Kurumbail RG, Marnett LJ (2003) A novel mechanism of cox-2 inhibition involving interactions with Ser-530 and Tyr-385. J Biol Chem 278:45763–45769

    Article  PubMed  CAS  Google Scholar 

  31. Saptarini NM, Sitorus EY, Levita J (2013) Structure based insilico study of 6-gingerol and 6-paradol active compounds of ginger (zingiber officinale) as COX-2 inhibitors. Int J Chem 5:12–18

    Article  CAS  Google Scholar 

  32. Sarika A, Purabi R, Vinod S, Avnish K, Singh R, Poonam S (2012) Anti-inflammatory activity of lactobacillus on carrageenan-induced paw edema in male Wistar rats. Int J Inflam. https://doi.org/10.1155/2012/752015

    Article  Google Scholar 

  33. Schonbeck U, Sukhova GK, Graber P, Coulter S, Libby P (1999) Augmented expression of Cyclooxygenase-2 in Human Atherosclerotic lesions. Am J Pathol 155:1281–1291

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Shaikh RU, Pund MM, Gacche RN (2015) Evaluation of anti-inflammatory activity of selected medicinal plants used in Indian traditional medication system in vitro as well as in vivo. J Tradit Complement Med 6:355–361

    Article  PubMed  PubMed Central  Google Scholar 

  35. Siracuse JJ, Chaikof EL (2012) The pathogenesis of diabetic atherosclerosis. In: Shrikhande GV, McKinsey JF (eds) Diabetes and pheripheral vascular disease: diagnosis and management, contemporary. Springer, New York, pp 13–26

    Chapter  Google Scholar 

  36. Stemme V, Swedenberg J, Claesson HE, Hansson GK (2000) Expression of cyclooxygenase-2 in human atherosclerotic carotid arteries. Eur J Vasc Endovasc Surg 20:146–152

    Article  PubMed  CAS  Google Scholar 

  37. Timofeevski SL, Prusakiwicz JJ, Rouzer CA, Marnett LJ (2002) Isoform-selective interaction of cox-2 with indomethacin amides studied by realtime fluorescene, inhibition kinetics and site directed mutagenesis. Biochemistry 41:9654–9662

    Article  PubMed  CAS  Google Scholar 

  38. Winter CA, Risley EA, Nuss GW (1962) Carrageenan induced edema in the hind paw of rats as an assay for anti-inflammatory activity. Proc Soc Exp Biol Med 111:544–547

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Dr. G. Shyam Prasad is thankful to University Grants Commission (UGC), New Delhi, India for providing Dr. D. S. Kothari fellowship (No. F.4-2/2006 (BSR)/13-962/2013 (BSR) at Department of Biochemistry, Osmania University, Hyderabad, Telangana State.

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Correspondence to R. B. Sashidhar.

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Prasad, G.S., Govardhan, P., Deepika, G. et al. Anti-inflammatory activity of anti-hyperlipidemic drug, fenofibrate, and its phase-I metabolite fenofibric acid: in silico, in vitro, and in vivo studies. Inflammopharmacol 26, 973–981 (2018). https://doi.org/10.1007/s10787-017-0428-y

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Keywords

  • COX-2
  • Fenofibrate
  • Fenofibric acid
  • Anti-inflammatory activity