Pharmacogenetic determinants of human liver microsomal aminopyrine metabolism and the role of cytochrome P450 2D6

Abstract :

Aminopyrine (AM) has been used as a model substrate for the investigation of drug metabolism. The major metabolic route N-demethylation was confirmed in liver microsomes. The present study aimed to identify the human cytochrome P-450 enzyme (CYP) mediating the N-demethylation of 4-di-methylaminoantipyrine (4-DMAA) to 4-methylaminoantipyrine (4-MAA). The contribution of human CYP to the metabolism of (4-DMAA) to (4-MAA) in humans was investigated using virus-expressed human CYP, and human liver microsomes with chemical inhibition studies. The substrate of 4-dimethylaminantipyrine was employed at different concentrations (11.5, 23, 46, 115 and 230 µmol per l) with varying concentrations of selective inhibitors of CYP (CYP1A2), (CYP3A4), (CYP2C8),(CYP2A6), (CYP2D6), (CYP2C19) and (CYP1A1). 4-DMAA and 4-MAA were analysed by HPLC and enzyme kinetic parameters (Km and Vmax) were calculated from the concentration data. The transformation of 4-dimethylaminoantipyrine to 4-methyaminoantipyrine by microsomes prepared from baculovirus-expressed human CYP was pronounced with CYP2D6. The metabolism of 4-dimethylaminoantipyrine was inhibited by 60.0% and 55.17% by a concentration of 100 µmo per l of the known CYP2D6 inhibitors quinidine and moclobemide. The corresponding Ki values were 0.050 and 0.11 mM, respectively. The corresponding IC50 values were 0.06 and 0.13 mM, respectively. The enzyme CYP2D6 has an important role in N-demethyl-ation of 4-dimethylaminoantipyrine.

References

1. Bonkowsky JL, Frazer JK, Buchi KF, Byington CL (2002) Metamizole use by Latino immigrants: a common and potentially harmful home remedy. Pediatrics. 109:e98. doi: 10.1542/peds.109.6.e98
2. Asmardi G, Jamali F (1983) High-performance liquid chromatography of dipyrone and its active metabolite in biological fluids. Journal of Chromatogrophy. 277: 183-189. doi: 10.1016/s0378-4347(00)84835-5
3. Levy M, Zylber-Katz E, Rosenkranz B (1995) Clinical pharmacokinetics of dipyrone and its metabolites. Clinical Pharmacokinetics. 28: 216-234. doi: 10.2165/00003088-199528030-00004
4. Blaisdell J, Mohrenweiser H, Jackson J, Ferguson S, Coulter S, Chanas B, Xi T, Ghanayem B, Goldstein JA (2002) Identification and functional characterization of new potentially defective alleles of human CYP2C19. Pharmacogenetics. 12: 703-711. doi: 10.1097/00008571-200212000-00004
5. Pereira PC, Barraviera B, Marcondes J, Leite CV, Meira DA, Inoue T, Morceli J (1985) Progressive subacute paracoccidioidomycosis. Treatment of a patient with amphotericin B and parenteral feeding. Revista do Institute de Medicina Tropical de Sao Paulo. 27 (50): 268-273. doi: 10.1590/s0036-46651985000500007
6. Nelson AC, Huang W, Moody DE (2001) Variables in human liver microsome preparation: impact on the kinetics of l-alpha-acetylmethadol (LAAM) n-demethylation and dextromethorphan O-demethylation. Drug Metabolism and Disposition. 29: 319-325. PMID: 11181502.
7. Tisi DK, Emard JJ, Koski KG (2004) Total protein concentration in human amniotic fluid is negatively associated with infant birth weight. Journal of Nutrition. 134: 1754-1758. doi.org/10.1093/jn/134.7.1754
8. Ip M, Lomas DA, Shaw J, Burnett D, Stockley RA (1990) Effect of non-steroidal anti-inflammatory drugs on neutrophil chemotaxis-an in vitro and in vivo study. British Journal of Rheumatology. 29 (5): 363-367. doi: 10.1093/rheumatology/29.5.363
9. Cheng Y, 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. Biochemical Pharmacology. 22 (23): 3099-3108. doi: 10.1016/0006-2952(73)90196-2
10. Nelson DR, Koymans L, Kamataki T, Stegeman JJ, Feyereisen R, Waxman DJ, Waterman MR, Gotoh O, Coon MJ, Estabrook RW, Gunsalus IC, Nebert DW (1996) P450 superfamily: update on new sequences, gene mapping, accession numbers and nomenclature. Pharmacogenetics. 6 (1): 1-42. doi: 10.1097/00008571-199602000-00002.
11. Miners JO, Birkett DJ (1998) Cytochrome P4502C9: an enzyme of major importance in human drug metabolism. Britsih Journal of Clinical Pharmacology. 45 (6): 525-538. doi: 10.1046/j.1365-2125.1998. 00721.x.
12. Huskey SW, Dean DC, Miller RR, Rasmusson GH and Chiu SH (1995) Identification of human cytochrome P450 isozymes responsible for the in vitro oxidative metabolism of finasteride. Drug Metabolism and Disposition. 23: 1126-1135. PMID: 8654202.
13. Flusser D, Zylber-Katz E, Granit L, Levy M (1988) Influence of food on the pharmacokinetics of dipyrone. European Journal of Clinical Pharmacology. 34 (1): 105-107. doi: 10.1007/BF01061429
14. Geisslinger G, Bocker R, Levy M (1996) High-performance liquid chromatographic analysis of dipyrone metabolites to study their formation in human liver microsomes. Pharmacological Research. 13 (8): 1272-1275. doi: 10.1023/a:1016088925786
15. Hemeryck A, Belpaire FM (2002) Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Current Drug Metabolism. 3 (1): 13-37. doi: 10.2174/1389200023338017
16. Shimada T, Yamazaki H, Mimura M, Inui Y, Guengerich FP (1994) Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. The journal of Pharmacology and Experimental Therapeutics. 270 (1): 414-423. PMID: 8035341.
17. Mizutani T (2003) PM frequencies of major CYPs in Asians and Caucasians. Drug Metabolism Reviews. 35 (2-3): 99-106. doi: 10.1081/dmr-120023681
18. Vlahov V, Badian M, Verho M, Bacracheva N (1990) Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium. European Journal of Clinical Pharmacology. 38 (1): 61-65. doi: 10.1007/BF00314805.
19. Wang B, Sanchez RI, Franklin RB, Evans DC, Huskey SE (2004) The involvement of CYP3A4 and CYP2C9 in the metabolism of 17 alpha-ethinylestradiol. Drug Metabolsim and Disposition. 32 (11): 1209-1212. doi: 10.1124/dmd.104.000182.
20. Naritomi Y, Terashita S, Kagayama A, 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 Metabolism and Disposition. 31 (5): 580-588. doi: 10.1124/dmd.31.5.580
21. Van Agtmael MA, Van Der Graaf CA, Dien TK, R P Koopmans RP, van Boxtel CJ (1998) The contribution of the enzymes CYP2D6 and CYP2C19 in the demethylation of artemether in healthy subjects. European Journal of Drug Metabolism and Pharmacokinetics. 23 (3): 429-36. doi: 10.1007/BF03192305

Citation :

Abdalla SOA (2022) Pharmacogenetic determinants of human liver microsomal aminopyrine metabolism and the role of cytochrome P450 2D6. Mediterr J Pharm Pharm Sci. 2 (1): 22-27. [Article number: 49]. https://doi.org/10.5281/zenodo.6399421