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 aminopyrine have been monitored in vivo in 60 healthy volunteers by measuring the amount of parent drug and metabolites recovered in the urine 24 h after oral administration of 250 mg aminopyrine. 2. The amount of metabolites in the 24-h urine was (mean +/- SD of 60 individuals): unchanged 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 interindividual differences (12-200-fold changes) are present in all the metabolic steps involved in aminopyrine biotransformation. These differences are not related to gender, intake of caffeine or alcohol, or known drug-metabolizing polymorphisms such as those involved in debrisoquine or mephenytoin metabolism. In contrast, smoking resulted in a decrease in the N(4)-demethylation ratio (p = 0.011). 4. The interindividual differences followed an apparently normal distribution in the N(4)- and N(2)-dimethylation and formylation pathways (p > 0.1). In contrast, acetylation follows a polymorphic distribution (p < 0.03), with an apparent antimode ratio close to 4. With the exception of the acetylation pathway, all of the metabolic ratios correlated between themselves (p < 0.001).