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Original Articles Open Access
Methylaminoantipyrine is a non-steroidal anti-inflammatory drug (NSAID), commonly used in the past as a powerful painkiller and fever reducer. It is better known under the brand names Neo-Melubrina®,Analgin®, and Novalgin®. Because of the risk of serious adverse effects, its use is justified only in serious situations where no alternative is available or suitable. Dipyrone is a widely used well tolerated analgesic drug which is how-ever compromised by agranulocytosis as adverse effect. Subsequent to no enzymatic hydrolysis, primary metabolic step is N-demethylation of 4-meth-ylaminoantipyrine (4-MAA) to 4-aminoantipyrine (4-AA). The aim of the present study was to identify the cytochrome P-450 enzyme (CYP) mediating this reaction. We identified the relevant CYP using virus expressed isolated rat liver microsomes with chemical inhibition studies. The substrate of 4- methylaminantipyrine was employed at six different concentrations (25, 50, 100, 400, 800 and 1200 μmol/l) with varying concentrations of selective inhibitors of CYP1A2 (furafylline, fluvoxamine), CYP3A4 (ketoconazole), CYP2A6 (coumarin), CYP2D6 (Quinidine), CYP2C19 (omeprazole,CYP2C9 (sulphaphenazole) and CYP1A1 (alpha -naphthoflavone). 4-MAA and 4-AA were analyzed by HPLC, and enzyme kinetic parameters (Km and Vmax) were determined by regression (Sig-ma plot 9.0. The N-demethylation of 4-MAA by microsomes prepared from baculovirus-expressing human CYP was pronounced with CYP2C19. Intrinsic clearance of the most active enzymes were 0.092, 0.027, and 0.026 for the CYP enzymes 2C19, 2D6 and 1A2 respectively. Metabolism by rat liver microsomes was strongly inhibited by omeprazole (IC50 of 0.05). The enzyme CYP2C19 apparently has an important role in N-demethylation of 4- methylaminoantipyrine which should be further analyzed in clinical studies and which may also be interesting concerning the agranulocytosis.
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Author(s): Salem O Ali Abdalla Thabet H Nagah Ashraf F Alzalitni and Fathiya Asteal
Dipyrone, 4-methylaminoantipyrine (4-MAA), 4- aminoantipyrine (4-AA), metabolism, Enzyme CYP2C19., genetic polymorphisms