Abstract
In the present study, we evaluated the anti-inflammatory activity with pharmacokinetic, ulcerogenic properties of various synthesized prodrugs of ibuprofen in experimental animals. Prodrugs 2, 6, 9, 10, 12, and 14 were found to possess significant anti-inflammatory activity with almost non-ulcerogenic potential than standard drug ibuprofen 1a in both normal and inflammation-induced rats. Metabolic stability of prodrugs 2, 6, 9, 10, 12, and 14 were also studied in rat liver microsomes and oral bioavailability was determined by estimating area under curve (AUC) and plasma concentration of these prodrugs at various time intervals. The experimental findings elicited higher AUC and plasma concentration at 1 and 2 h indicating improved oral bioavailability as compared to parent ibuprofen. These prodrugs are found to have least gastric ulceration with retain anti-inflammatory activity observed in experimental animals. Therefore, present experimental findings demonstrated significant improvement of various pharmacokinetic properties with least ulcerogenic potential of ester prodrugs of ibuprofen an anti-inflammatory agent
Similar content being viewed by others
Abbreviations
- NSAID:
-
Nonsteroidal anti-inflammatory drug
- Tris–HCl:
-
Tris(hydroxymethyl)aminomethane hydrochloride
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- HPLC:
-
High performance liquid chromatography
- GC:
-
Gas chromatography
- RLM:
-
Rat liver microsomes
- RP:
-
Rat plasma
- API:
-
Active pharmaceutical ingredient
- UI:
-
Ulcer index
- GI:
-
Gastrointestinal
- DMAc:
-
Dimethyl acetamide
- PTSA:
-
p-Toluene sulfonic acid
- PXRD:
-
Powder X-ray diffraction
- RT:
-
Room temperature
- TMG:
-
1,1,3,3-Tetramethyl guanidine
- 18 Crown 6:
-
1,4,7,10,13,16-Hexaoxacyclooctadecane
- EP:
-
European pharmacopoeia
- Ar:
-
Aromatic
- BDL:
-
Below detection limit
References
Abordo EA, Bowden K, Huntington AP, Powell SL (1998) Prodrugs. Part 3. 2-Formylphenyl esters of indomethacin, ketoprofen and ibuprofen and 6-substituted 2-formyl and 2-acylphenyl esters of aspirin. Farmaco 53:95–101
Ashraf E, Ford L, Geetha R, Cooper S (1999) Safety profile of ibuprofen suspension in young children. Inflammopharmacology 7:219–225
Bhosale D, Bharambe S, Gairola N, Dhaneshware SS (2006) Mutual prodrug concept: fundamentals and applications. Ind J Pharm Sci 3:286–294
Borhade N, Pathan AR, Halder S, Karwa M et al (2012) NO-NSAIDs. Part 3: Nitric oxide-releasing prodrugs of non-steroidal anti-inflammatory drugs. Chem Pharm Bull 60:465–481
Bresalier RS, Sandler RS, Quan H, Bolognese JA, Oxenius B, Horgan K, Lines C, Riddell R, Morton D, Lanas A, Konstam MA, Baron JA (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med 352:1092–1102
Bundgaard H (ed) (1986) Design of prodrugs. Elsevier, Amsterdam, pp 49–68
Bundgaard H (1989) The double prodrug concept and its applications. Adv Drug Rev 3:39–65
Chen Q, Gong T, Liu J, Wang X, Fu H, Zhang Z (2009) Synthesis, in vitro and in vivo characterization of glycosyl derivatives of ibuprofen as novel prodrugs for brain drug delivery. J Drug Target 17:318–328
Cioli V, Putzolu S, Rossi V, Corradino CA (1980) Toxicological and pharmacological study of ibuprofen guaiacol ester (AF 2259) in the rat. Toxicol Appl Pharmacol 54:332–339
Coruzzi G, Venturi N, Spaggiarim S (2007) Gastrointestinal safety of novel nonsteroidal anti-inflammatory drugs: selective COX-2 inhibitors and beyond. Acta Biomed 78:96–110
Crunckhon P, Meacock SER (1971) Mediators of inflammation induced in rat paw edema by carrageenan. Br J Pharmacol 42:392–402
Gairola N, Nagpal D, Dhaneshwar SS, Dhaneshwar SR, Chaturvedi SC (2005) Synthesis, hydrolysis kinetics and pharmacodynamic profile of novel prodrugs of flurbiprofen. Indian J Pharm Sci 67:369–373
Ganguly AK, Bhatnagar OP (1973) Effect of bilateral adrenalactomy on production of resistant ulcers in the stomach of albino rats. Can J Physiol Pharmacol 51:748–750
Halen PK, Murumkar PR, Giridhar R, Yadav MR (2009) Prodrug designing of NSAIDs. Mini-reviews in medicinal chemistry 9:124–139
Huang Z, Velazquez CA, Abdellatif KRA, Chowdhury MA, Reisz JA, DuMond JF, Bruce King S, Knaus EE (2011) Ethanesulfohydroxamic acid ester prodrugs of nonsteroidal antiinflammatory drugs (NSAIDs): synthesis, nitric oxide and nitroxyl release, cyclooxygenase inhibition, anti-inflammatory, and ulcerogenicity index studies. J Med Chem 54:1356–1364
Kawail S, Kojima F, Kusunoki N (2005) Recent advances in non-steroidal anti-inflammatory drugs. Allergol Int 54:209–215
Kean WF, Buchanan WW (2005) The use of NSAIDs in rheumatic disorders 2005: a global perspective. Inflammopharmacol 13:343–370
Kim H, Jeon H, Kong H, Yang Y, Choi B, Kim YM, Neckers L, Jung YA (2006) Molecular mechanism for the anti-inflammatory effect of taurine-conjugated 5-aminosalicylic acid in inflamed colon. Mol Pharmacol 69:1405–1412
Klasser GD, Epstein J (2005) Nonsteroidal anti-inflammatory drugs: confusion, controversy and dental implications. J Can Dent Assoc 71:575–580
Mahfouz NM, Omar FA, Aboul-Fadl T (1999) Cyclic amide derivatives as potential prodrugs II: n-hydroxymethylsuccinimide isatin esters of some NSAIDs as prodrugs with an improved therapeutic index. Eur J Med Chem 34:551–562
Nielsen NM, Bundgaard H (1988) Glycolamide esters as biolabile prodrugs of carboxylic acid agents: synthesis, stability, bioconversion, and physicochemical properties. J Pharm Sci 77:285–298
Nussmeier NA, Whelton AA, Brown MT, Langford RM, Hoeft A, Parlow JL, Boyce SW, Verburg KM (2005) Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 352:1081–1091
OECD (2006) Organization of Economic and Corporation Development guidelines for the testing of chemicals-acute oral toxicity up and down procedure. p 425
Perioli L, Ambrogi V, Bernardini C, Grandolini G, Ricci M, Giovagnoli S, Rossi C (2004) Potential prodrugs of non-steroidal anti-inflammatory agents for targeted drug delivery to the CNS. Eur J Med Chem 39:715–727
Rainsford KD (1988) Gastrointestinal damage from nonsteroidal anti-inflammatory drugs toxicol. Pathology 16:251–259
Shaaya O, Magora A, Sheskin T, Kumar N, Domb A (2003) Anhydride prodrugs for nonsteroidal anti-inflammatory drugs. J Pharm Res 20:205–211
Shanbhag VR, Rider AM, Gokhale R, Harpalanai A, Dick RM (1992) Ester and amide prodrugs of ibuprofen and naproxen: synthesis, anti-inflammatory activity, and gastrointestinal toxicity. J Pharm Sci 81:149–154
Wallace JL (1994) The 1994 Merck Frosst Award. Mechanisms of nonsteroidal anti-inflammatory drug (NSAID) induced gastrointestinal damage potential for development of gastrointestinal tract safe NSAIDs. Can J Physiol Pharmacol 72:1493–1498
Winter CA, Porter CC (1957) Effect of alteration in side chain on anti-inflammatory and liver glycogen activities of hydrocortisone exters. Am J Pharm Sci 46:515–520
Winter CA, Risley EA, Nuss GW (1962) Carrageenan induced edema in hind paw of rats as an assay for anti-inflammatory drugs. Proc Soc Exp Biol Med 111:544–547
Acknowledgments
The authors also gratefully acknowledge the support extended by Mr. Ashok Hiremath, Managing Director, Astec Lifesciences Ltd. Authors are also thankful to Dr. S. R. Naik and Dr. S.B. Bhise, Sinhgad Institute of Pharmaceutical Sciences, Lonavala for providing necessary facility for pharmacological experimentation.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Dhakane, V.D., Chavan, H.V., Thakare, V.N. et al. Novel ibuprofen prodrugs with improved pharmacokinetics and non-ulcerogenic potential. Med Chem Res 23, 503–517 (2014). https://doi.org/10.1007/s00044-013-0639-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00044-013-0639-8