The acetylation phenotype: does it contribute to the non-linearity of the metabolite pharmacokinetics of metamizol?

Abstract

The non-narcotic analgesic metamizol (noramidopyrine, dipyrone) is a typical prodrug. After oral administration, metamizol is completely hydrolysed in the gastro-intestinal tract to the pharmacologically active metabolite 4-methyl-amino-antipyrine (4-MAA). The main metabolic pathways for 4-MAA are consistent with 1) oxidation to 4-formyl-amino-antipyrine (4-FAA), and 2) demethylation to 4-amino-antipyrine (4-AA), which is further acetylated to 4-acteyl-amino-antipyrine (4-AcAA). The four metabolites of metamizol account for 65-70 % of the dose [1]. A previous investigation revealed that the pharmacokinetics of the metabolites was linear up to a dose of 1.5 g metamizol. An increase in dose to 3.0 g produced a greater increase in the areas under the serum concentration-time curve of 4-MAA, and a decrease in the formation of 4-FAA. The larger amount of 4-MAA resulted in a corresponding increase in the formation of further metabolites, such as 4-AA and 4-AcAA [2]. Since the conversion of 4-AA to 4-AcAA is produced by the polymorphic Nacetyl-transferase system [3], a greater deviation from linearity of 4-MAA pharmacokinetics can be assumed for slow acetylators than for rapid acetylators.The present study is based on reassessment of the data with regard to the acetylation ability of the participants and aims to give further information on the influence of acetylation phenotype on metabolite pharmacokinetics with increasing doses of metamizol.The participants were 15 healthy volunteers, who received single oral doses of 0.75, 1.5 and 3.0 g metamizol (1.5, 3 and 6 tablets Novalgin, Hoechst AG, Germany) on three different occasions, at 7 day-intervals [2]. The N. Bacracheva ([~). V. Vlahov Department of Clinical Pharmacology, Medical Faculty, University Hospital "Queen Giovanna", 8 Belo more Street, 1040 Sofia, Bulgaria serum and urine concentrations of the metabolites were determined using an HPLC method [4].Acetylation phenotyping of the participants was carried out according to the Zylber- Katz et al. (1992) [5] method, using the serum concentration ratio of 4-AcAA/4-AA 6 h after metamizol ingestion. Eight of the subjects were rapid [mean 6.77 (3.64)] and five were slow [mean 0.62 (0.18)] acetylators. Two of the participants were considered to be of intermediate type (mean 1.6) and were not included in the analysis.The influence of acetylation phenotype on the linearity of the pharmacokinetics of the metabolites of metamizol was evaluated using two parameters: the serum concentration-time curves (AUC) and the formation rates of the metabolites. The AUC's were calculated according to standard procedures [2]. The rates of formation of 4-FAA, 4-AA and 4-AcAA were expressed as clearance for production (eLm) of the metabolites and were calculated according to the formula CL m --Ae/AUCp, in which A e is the amount of metabolite excreted in urine, and AUCp is the area under the serum concentration-time curve of the precursor of the metabolite [6]. In the case of 4-MAA, non-renal clearance was used instead of the formation rat...

Metamizole: A Review Profile of a Well-Known “Forgotten” Drug. Part I: Pharmaceutical and Nonclinical Profile

“…the enzyme likely to be responsible for MAA metabolism, is cytochrome P450 3A4 (19). the metabolism of metamizole is not influenced by the acetylation phenotype (5,56).…”

Metamizole (Dipyrone) and the Liver: A Review of the Literature

“…However, increasing doses of metamizole do not lead to a deviation from linearity in AUC or formation rate in slow acetylators compared to rapid acetylators. Therefore, it must be assumed that despite the increasing plasma concentrations of 4‐AA associated with increasing metamizole doses, no saturation of acetylation capacity from 4‐AA to 4‐AAA occurs even if it is genetically low, as in slow acetylators …”

“…Therefore, it must be assumed that despite the increasing plasma concentrations of 4-AA associated with increasing metamizole doses, no saturation of acetylation capacity from 4-AA to 4-AAA occurs even if it is genetically low, as in slow acetylators. 76,77 Besides the metamizole metabolites mentioned above, which have been known for decades, 2 further metabolites have been identified more recently by liquid chromatography-mass spectrometry-based analyses after oral administration of metamizole to mice: arachidonoyl-4-MAA and arachidonoyl-4-AA, representing the arachidonoyl amides of 4-MAA and 4-AA, respectively. 73,78 Furthermore, a total of 6 metabolites of metamizole could be detected in the urine of healthy volunteers after oral administration of metamizole.…”