Human metabolism of 7-substituted theophyllines: N3-demethylation and lack of oxidation of proxyphylline.

Proxyphylline metabolism after oral administration to humans was studied. The only metabolic process detected was N3-demethylation, and 1-methyl-7-(2-hydroxypropyl)xanthine was isolated and identified. Proxyphylline was excreted in urine both an unchanged compound (12.7% of dose) and as its metabolic product (30.2% of dose). The latter substance was not found (detection limit = 1 microgram/ml) in the systemic circulation. Thus, it probably does not participate in the pharmacological activity of proxyphylline in vivo, although it was as active as the parent drug in relaxing the guinea pig tracheal chain. Lack of metabolism to uric acid derivatives is explained by the low affinity of both substances toward the enzymes the oxidize xanthine (xanthine oxidase) and methylxanthine derivatives. The presence of the metabolite in urine interferes with some analytical methods developed for estimation of unchanged proxyphylline. Published data on the urinary excretion of this drug need reevaluation.