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Metabolic chiral inversion of 2-arylpropionic acid derivatives (profens)
Affiliations- Department of Laboratory Medicine, Faculty of Pharmacy, Collegium Medicum, Nicolaus Copernicus University, Bydgoszcz, Poland
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Abstract
2-arylpropionic acid derivatives (profens) are one of the most popular anti-inflammatory, analgesic, and antipyretic drugs. They belong to a group of nonsteroidal anti-inflammatory drugs (NSAID) and exhibit metabolic chiral inversion. Enantiomers of these chiral drugs are often characterised by different pharmacological activity. It is estimated that the values of metabolic chiral inversion of (R)-ibuprofen in humans are between 35 and 70%, depending on the condition of the liver and the intake of other medicines, while (R)-flurbiprofen undergoes chiral metabolic inversion to its opposed (S) form only in small range. The described phenomenon in the case of (R)-ketoprofen is limited to a maximum of around 10%. The metabolic chiral inversion is associated with potentially important pharmacotherapeutic and toxicological consequences, and so an attempt was made to analyse this phenomenon for the most commonly used drugs from the profens group.
Abstract
2-arylpropionic acid derivatives (profens) are one of the most popular anti-inflammatory, analgesic, and antipyretic drugs. They belong to a group of nonsteroidal anti-inflammatory drugs (NSAID) and exhibit metabolic chiral inversion. Enantiomers of these chiral drugs are often characterised by different pharmacological activity. It is estimated that the values of metabolic chiral inversion of (R)-ibuprofen in humans are between 35 and 70%, depending on the condition of the liver and the intake of other medicines, while (R)-flurbiprofen undergoes chiral metabolic inversion to its opposed (S) form only in small range. The described phenomenon in the case of (R)-ketoprofen is limited to a maximum of around 10%. The metabolic chiral inversion is associated with potentially important pharmacotherapeutic and toxicological consequences, and so an attempt was made to analyse this phenomenon for the most commonly used drugs from the profens group.
Keywords
metabolic chiral inversion, ibuprofen, flurbiprofen, ketoprofen, naproxen, chiral drugs, enantiomers
About this articleTitle
Metabolic chiral inversion of 2-arylpropionic acid derivatives (profens)
Journal
Issue
Article type
Review article
Pages
1-5
Published online
2017-09-21
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1432
Article views/downloads
2205
DOI
Bibliographic record
Medical Research Journal 2017;2(1):1-5.
Keywords
metabolic chiral inversion
ibuprofen
flurbiprofen
ketoprofen
naproxen
chiral drugs
enantiomers
Authors
Joanna Siódmiak
Tomasz Siódmiak
Agata Tarczykowska
Katarzyna Czirson
Jacek Dulęba
Michał Piotr Marszałł
References (32)- Wu L, Vogt FG. A review of recent advances in mass spectrometric methods for gas-phase chiral analysis of pharmaceutical and biological compounds. J Pharm Biomed Anal. 2012; 69: 133–147.
- Siódmiak T, Ziegler-Borowska M, Marszałł M. Lipase-immobilized magnetic chitosan nanoparticles for kinetic resolution of (R,S)-ibuprofen. Journal of Molecular Catalysis B: Enzymatic. 2013; 94: 7–14.
- Siodmiak T, Ruminski JK, Marszall MP. Application of Lipases from Candida rugosa in the Enantioselective Esterification of (R,S)-Ibuprofen. Current Organic Chemistry. 2012; 16(8): 972–977.
- Wsól V, Skálová L, Szotáková B. Chiral inversion of drugs: coincidence or principle? Curr Drug Metab. 2004; 5(6): 517–533.
- Tegeder I, Williams K, Geisslinger G. Metabolic Chiral Inversion of 2-Arylpropionic Acids. In: Eichelbaum M, Testa B, Somogyi A. ed. Stereochemical Aspects of Drug Action and Disposition. Springer, Berlin–Heidelberg 2003: 341–354.
- Neupert W, Brugger R, Euchenhofer C, et al. Effects of ibuprofen enantiomers and its coenzyme A thioesters on human prostaglandin endoperoxide synthases. Br J Pharmacol. 1997; 122(3): 487–492.
- Rainsford KD. Ibuprofen: A Critical Bibliography Review. Taylor &Francis, London 1999: London.
- Bonabello A, Galmozzi MR, Canaparo R, et al. Dexibuprofen (S+-isomer ibuprofen) reduces gastric damage and improves analgesic and antiinflammatory effects in rodents. Anesth Analg. 2003; 97(2): 402–408.
- Davies N. Clinical Pharmacokinetics of Ibuprofen. Clinical Pharmacokinetics. 1998; 34(2): 101–154.
- Rousseau A, Chiap P, Ivanyi R, et al. Validation of a nonaqueous capillary electrophoretic method for the enantiomeric purity determination of R-flurbiprofen using a single-isomer amino cyclodextrin derivative. J Chromatogr A. 2008; 1204(2): 219–225.
- Wechter WJ, Leipold DD, Quiggle DD, et al. R-Flurbiprofen (E-7869), a chemopreventive and treatment of cancer. InflammoPharmacology. 2000; 8(2): 189–206.
- Lammers I, Lhiaubet-Vallet V, Consuelo Jiménez M, et al. Stereoselective binding of flurbiprofen enantiomers and their methyl esters to human serum albumin studied by time-resolved phosphorescence. Chirality. 2012; 24(10): 840–846.
- Martin JE, Le Leu RK, Hu Y, et al. R-flurbiprofen suppresses distal nonmucin-producing colorectal tumors in azoxymethane-treated rats, without suppressing eicosanoid production. Am J Physiol Gastrointest Liver Physiol. 2010; 298(6): G860–G864.
- Ciou JF, Wang PY, Wu AC, et al. Lipase-catalyzed alcoholytic resolution of (R,S)-flurbiprofenyl azolides for preparation of (R)-NO-flurbiprofen ester prodrugs. Process Biochemistry. 2011; 46(4): 960–965.
- Quann EJ, Khwaja F, Zavitz KH, et al. The aryl propionic acid R-flurbiprofen selectively induces p75NTR-dependent decreased survival of prostate tumor cells. Cancer Res. 2007; 67(7): 3254–3262.
- Wynne S, Djakiew D. NSAID inhibition of prostate cancer cell migration is mediated by Nag-1 Induction via the p38 MAPK-p75(NTR) pathway. Mol Cancer Res. 2010; 8(12): 1656–1664.
- Jin H, Wang Z, Liu L, et al. R-flurbiprofen reverses multidrug resistance, proliferation and metastasis in gastric cancer cells by p75(NTR) induction. Mol Pharm. 2010; 7(1): 156–168.
- Tamborini L, Romano D, Pinto A, et al. An efficient method for the lipase-catalysed resolution and in-line purification of racemic flurbiprofen in a continuous-flow reactor. Journal of Molecular Catalysis B: Enzymatic. 2012; 84: 78–82.
- Liu JK, Patel SK, Gillespie DL, et al. R-flurbiprofen, a novel nonsteroidal anti-inflammatory drug, decreases cell proliferation and induces apoptosis in pituitary adenoma cells in vitro. J Neurooncol. 2012; 106(3): 561–569.
- Landoni MF, Lees P. Pharmacokinetics and pharmacodynamics of ketoprofen enantiomers in the horse. J Vet Pharmacol Ther. 1996; 19(6): 466–474.
- Jamali F, Brocks D. Clinical Pharmacokinetics of Ketoprofen and Its Enantiomers. Clinical Pharmacokinetics. 1990; 19(3): 197–217.
- Adachi H, Ioppolo F, Paoloni M, et al. Physical characteristics, pharmacological properties and clinical efficacy of the ketoprofen patch: a new patch formulation. Eur Rev Med Pharmacol Sci. 2011; 15(7): 823–830.
- Hutt AJ, Caldwell J. The importance of stereochemistry in the clinical pharmacokinetics of the 2-arylpropionic acid non-steroidal anti-inflammatory drugs. Clin Pharmacokinet. 1984; 9(4): 371–373.
- Foster RT, Jamali F. High-performance liquid chromatographic assay of ketoprofen enantiomers in human plasma and urine. J Chromatogr. 1987; 416(2): 388–393.
- Rudy AC, Liu Y, Brater C, et al. Stereoselective pharmacokinetics and inversion of (R)- ketoprofen in healthy volunteers. J Clin Pharmacol. 1998; 38(2 Suppl): 3S–310S.
- Kommuru TR, Khan MA, Reddy IK. Racemate and enantiomers of ketoprofen: phase diagram, thermodynamic studies, skin permeability, and use of chiral permeation enhancers. J Pharm Sci. 1998; 87(7): 833–840.
- Lagrange F, Pehourcq F, Bannwarth B, et al. Passage of S-(+)- and R-(-)-ketoprofen across the human isolated perfused placenta. Fundam Clin Pharmacol. 1998; 12(3): 286–291.
- Suzuki T, Kosugi Y, Hosaka M, et al. Occurrence and behavior of the chiral anti-inflammatory drug naproxen in an aquatic environment. Environ Toxicol Chem. 2014; 33(12): 2671–2678.
- Camacho-Muñoz D, Petrie B, Castrignanò E, et al. Enantiomeric Profiling of Chiral Pharmacologically Active Compounds in the Environment with the Usage of Chiral Liquid Chromatography Coupled with Tandem Mass Spectrometry. Curr Anal Chem. 2016; 12(4): 303–314.
- Capone ML, Tacconelli S, Di Francesco L, et al. Pharmacodynamic of cyclooxygenase inhibitors in humans. Prostaglandins Other Lipid Mediat. 2007; 82(1-4): 85–94.
- Zhang J, Hou Z, Yao C, et al. Purification and properties of lipase from a Bacillus strain for catalytic resolution of (R)-Naproxen. Journal of Molecular Catalysis B: Enzymatic. 2002; 18(4-6): 205–210.
- Jackson M, Labeda D, Becker L. Enantioselective hydrolysis of ethyl 2-hydroxyalkanoates by an extracellular esterase from a Bacillus sphaericus strain. Enzyme and Microbial Technology. 1995; 17(2): 175–179.