EFFECT OF CIMETIDINE ON THE PHARMACOKINETICS OF THE METABOLITES OF METAMIZOL

Metamizol (dipyrone) is hydrolyzed in the gastrointestinal tract to th e pharmacologically active metabolite 4-methyl-amino-antipyrine (4-MAA ), which is transformed by both, oxidation to 4-formyl-amino-antipyrin e (4-FAA) and demethylation to 4-amino-antipyrine (4-AA). 4-AA is acet ylated to 4-acetyl-amino-antipyrine (4-AcAA). The aim of the present s tudy was to investigate whether cimetidine will alter the pharmacokine tics of the metabolites of metamizol due to cimetidine-induced inhibit ion of the metabolic transformation of 4-MAA. The study was carried ou t in 12 patients with duodenal ulcer treated with cimetidine 1,000 mg daily over 20 days. A single oral dose of metamizol 1,500 mg was admin istered 2 days prior to commencement of cimetidine therapy to all pati ents. Two further doses of 750 and 1,500 mg of metamizol were given in a randomized order on days 8 and 13 during cimetidine treatment. Bloo d samples for determination of metamizol metabolites were drown over 4 8 hours post dose. Drug assays for metamizol metabolites and cimetidin e were performed using HPLC methods, The patients were phenotyped for CYP2D6 and acetylation polymorphism. The results revealed that cimetid ine interacted with 4-MAA by increasing the systemic availability, pro longing the elimination half-life and decreasing the systemic clearanc e of 4-MAA, whereas the renal clearances of 4-MAA remained unchanged. Consistent with cimetidine-induced changes in the oxidation of 4-MAA t o 4-FAA, as well as in the demethylation of 4-MAA to 4-AA, were the de creased rates of production and the lower maximum concentrations of 4- FAA and 4-AA when metamizol was administered during cimetidine treatme nt (p < 0.05). No correlation was found between the decrease in the pr oduction rates of 4-FAA induced by cimetidine and the hydroxylation ab ilities of the patients, this suggesting that CYP2D6 is not involved i n the metabolism of 4-MAA to 4-FAA. The acetylation of 4-AA to 4-AcAA was not affected by cimetidine. Cimetidine produced an increase not pr oportional to the dose in the systemic availability only of 4-MAA, whe reas the kinetics of the other metabolites changed proportionally to t he increasing dose of metamizol.