Identification of human cytochrome P450 isozymes responsible for the in-vitro oxidative demethylation of 4-methylaminoantipyrine
DOI:
https://doi.org/10.54361/Keywords:
Metamizole, 4-methylaminoantipyrine, 4-aminoantipyrine (4-AA), metabolism, CYP2C19Abstract
The aim of this study is to identify human cytochrome P-450 enzyme (CYP) mediating the oxidative N-demethylation of 4-methylaminoantipyrine (4-MAA) to 4-amino-antipyrine (4-AA). The contribution of human CYP to the metabolism of 4-MAA to 4-AA in human was investigated by using virus expressed human CYP, human liver microsomes and rat liver microsomes with chemical inhibition studies. The substrate of 4-methylaminantipyrine was employed at five different concentrations (12.5, 23, 46, 115 and 230 µmol/l) with varying concentrations of selective inhibitors of CYP (CYP1A2), (CYP3A4), (CYP2C8), (CYP2A6), (CYP2D6), (CYP2C19) and (CYP1A1). 4- MAA and 4-AA were analyzed by HPLC and enzyme kinetic parameters (Km and Vmax) were calculated from the concentration data. The transformation of 4-methylaminoantipyrine to 4- aminoantipyrine by microsomes prepared from baculovirus-expressed human CYP was pronounced with CYP2C19. Metabolism of 4-methylaminoantipyrine by human liver microsomes and rat liver microsomes was strongly inhibited by tranylcypromine, fluvoxamine and omeprazole inhibition was observed with other CYP selective inhibitors. 4-methyl-aminoantipyrine was also evaluated as a CYP substrate in rat liver microsomes. No significant inhibition of CYP1A2, CYP1A1, CYP3A4, CYP2C9, CYP2D6, CYP2A6 and CYP2E1 was observed in experiments (IC50 > 269.14 µM) but IC50 for CYP2C19 was 68.48 µM. In conclusion, the enzyme CYP2C19 apparently has an important role in N-demethylation of 4- methylaminoantipyrine.
Downloads
References
Bonkowsky JL, Frazer JK, Buchi KF and Byington CL. Metamizole use by Latino immigrants: a common and potentially harmful home remedy. Pediatrics. 2002, 109:e98.
Pereira PC, Barraviera B, Marcondes J, Leite CV, Meira DA, Inoue T and Morceli J. Progressive subacute paracoccidioidomycosis, treatment of a patient with amphotericin B and parenteral feeding. Rev Inst Med Trop Sao Paulo. 1985, 27: 268-273.
Sadusk JF. Planning in the food and drug administration for regulation of prescription drug advertising. Curr Ther Res Clin Exp. 1965, 18: 332-336.
Levy M. Pharmacokinetics of metamizol metabolites. Agents Actions. 1986, 19S: 199- 204.
Nelson AC, Huang W and Moody DE. Variables in human liver microsome preparation: impact on the kinetics of l-alpha-acetylmethadol (LAAM) n-demethylation and dextrom- ethorphan O-demethylation. Drug Metab Dispos. 2001, 29: 319-325.
Huskey SW, Dean DC, Miller RR, Rasmusson GH and Chiu SH. Identification of human cytochrome P450 isozymes responsible for the in vitro oxidative metabolism of finasteride. Drug Metab Dispos. 1995, 23: 1126-1135.
Tisi DK, Emard JJ and Koski KG. Total protein concentration in human amniotic fluid is negatively associated with infant birth weight. J Nutr. 2004, 134: 1754-1758.
Asmardi G and Jamali F. High-performance liquid chromatography of dipyrone and its active metabolite in biological fluids. J Chromatogr. 1983, 277: 183-189.
Geisslinger G, Bocker R and Levy M. High-performance liquid chromatographic analysis of dipyrone metabolites to study their formation in human liver microsomes. Pharm Res. 1996, 13: 1272-1275.
Salsali M, Holt A and Baker GB. Inhibitory effects of the monoamine oxidase inhibitor tranylcypromine on the cytochrome P450 enzymes CYP2C19, CYP2C9, and CYP2D6. Cell Mol Neurobiol. 2004, 24: 63-76.
Hemeryck A and Belpaire FM. Selective serotonin reuptake inhibitors and cytochrome P- 450 mediated drug-drug interactions: an update. Curr Drug Metab. 2002, 3: 13-37.
Blaisdell J, Mohrenweiser H, Jackson J, Ferguson S, Coulter S, Chanas B, Xi T, Ghanayem B and Goldstein JA. Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics. 2002, 12: 703-711.
Brune K and Otterness I (1988) In vivo and in vitro assessment of non-steroidal anti- inflammatory drugs. Baillieres Clin Rheumatol 2:295-307.
Cheng Y and Prusoff WH (1973) Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol 22:3099-3108.
Flusser D, Zylber-Katz E, Granit L and Levy M (1988) Influence of food on the pharmacokinetics of dipyrone. Eur J Clin Pharmacol 34:105-107.
Levy M, Zylber-Katz E and Rosenkranz B (1995) Clinical pharmacokinetics of dipyrone and its metabolites. Clin Pharmacokinet 28:216-234.
Naritomi Y, Terashita S, Kagayama A and Sugiyama Y (2003) Utility of hepatocytes in predicting drug metabolism: comparison of hepatic intrinsic clearance in rats and humans in vivo and in vitro. Drug Metab Dispos 31:580-588.
Vlahov V, Badian M, Verho M and Bacracheva N (1990) Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium. Eur J Clin Pharmacol 38:61-65.
Volz M and Kellner HM (1980) Kinetics and metabolism of pyrazolones (propyphenazone, aminopyrine and dipyrone). Br J Clin Pharmacol 10 Suppl 2:299S- 308S.
Wang B, Sanchez RI, Franklin RB, Evans DC and Huskey SE (2004) The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol. Drug Metab Dispos 32:1209-1212.
Downloads
Published
Issue
Section
License
Copyright (c) 2014 Salem Omran Ali Abdalla (Author)
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
Open Access Policy
Libyan journal of medical Research (LJMR).is an open journal, therefore there are no fees required for downloading any publication from the journal website by authors, readers, and institution.
The journal applies the license of CC BY (a Creative Commons Attribution 4.0 International license). This license allows authors to keep ownership f the copyright of their papers. But this license permits any user to download , print out, extract, reuse, archive, and distribute the article, so long as appropriate credit is given to the authors and the source of the work.
The license ensures that the article will be available as widely as possible and that the article can be included in any scientific archive.
Editorial Policy
The publication of an article in a peer reviewed journal is an essential model for Libyan journal of medical Research (LJMR). It is necessary to agree upon standards of expected ethical behavior for all parties involved in the act of publishing: the author, the journal editorial, the peer reviewer and the publisher.
Any manuscript or substantial parts of it, submitted to the journal must not be under consideration by any other journal. In general, the manuscript should not have already been published in any journal or other citable form, although it may have been deposited on a preprint server. Authors are required to ensure that no material submitted as part of a manuscript infringes existing copyrights, or the rights of a third party.
Authorship Policy
The manuscript authorship should be limited to those who have made a significant contribution and intellectual input to the research submitted to the journal, including design, performance, interpretation of the reported study, and writing the manuscript. All those who have made significant contributions should be listed as co-authors.
Others who have participated in certain substantive aspects of the manuscript but without intellectual input should only be recognized in the acknowledgements section of the manuscript. Also, one of the authors should be selected as the corresponding author to communicate with the journal and approve the final version of the manuscript for publication in the LJMR.
Peer-review Policy
- All the manuscripts submitted to LJMR will be subjected to the double-blinded peer-review process;
- The manuscript will be reviewed by two suitable experts in the respective subject area.
- Reports of all the reviewers will be considered while deciding on acceptance/revision or rejection of a manuscript.
- Editor-In-Chief will make the final decision, based on the reviewer’s comments.
- Editor-In-Chief can ask one or more advisory board members for their suggestions upon a manuscript, before making the final decision.
- Associate editor and review editors provide administrative support to maintain the integrity of the peer-review process.
- In case, authors challenge the editor’s negative decision with suitable arguments, the manuscript can be sent to one more reviewer and the final decision will be made based upon his recommendations.
