METABOLISM OF AMINOPYRINE AND DERIVATIVES IN MAN - IN-VIVO STUDY OF MONOMORPHIC AND POLYMORPHIC METABOLIC PATHWAYS

1. The main metabolic pathways involved in the biodisposition of amino pyrine have been monitored in vivo in 60 healthy volunteers by measuri ng the amount of parent drug and metabolites recovered in the urine 24 h after oral administration of 250 mg aminopyrine. 2. The amount of m etabolites in the 24-h urine was (mean +/- SD of 60 individuals): unch anged aminopyrine, 0.2 +/- 0.2 mg; methyl aminoantipyrine, 4.5 +/- 2.8 mg; formyl aminoantipyrine, 18.5 +/- 10.1 mg; aminoantipyrine, 9.2 +/ - 6.6 mg; and acetyl aminoantipyrine, 31.8 +/- 21.1 mg. 3. Large inter individual differences (12-200-fold changes) are present in all the me tabolic steps involved in aminopyrine biotransformation. These differe nces are not related to gender, intake of caffeine or alcohol, or know n drug-metabolizing polymorphisms such as those involved in debrisoqui ne or mephenytoin metabolism. In contrast, smoking resulted in a decre ase in the N(4)-demethylation ratio (p = 0.011). 4. The interindividua l differences followed an apparently normal distribution in the N(4)- and N(2)-demethylation and formylation pathways (p > 0.1). In contrast , acetylation follows a polymorphic distribution (p < 0.03), with an a pparent antimode ratio close to 4. With the exception of the acetylati on pathway, all of the metabolic ratios correlated between themselves (p < 0.001).