Abstract

Paraxanthine (PX; 1,7-dimethylxanthine) is the major metabolite of caffeine in humans. Despite the continuous exposure of a large proportion of the population to PX, little is known about PX disposition in humans. The present study was performed to define the metabolic partial clearances of PX in humans and, by determining the effects of cimetidine and allopurinol pretreatments on PX disposition, assess the relative importance of cytochrome P-450 and xanthine oxidase in PX biotransformation. The combined formation of the 7-demethylated products 1-methylxanthine (1-MX), 1-methyluric acid (1-MU) and 5-acetyl-amino-6-formylamino-3-methyluracil (AFMU) accounted for 67% of PX clearance. Formation of 7-methylxanthine (7-MX) and 1,7-dimethyluric acid and renal excretion of unchanged PX comprised 6, 8 and 9% of PX clearance, respectively. Allopurinol pretreatment had no effect on PX plasma clearance but decreased 1-MU excretion and increased 1-MX excretion, with the combined excretion of these metabolites remaining constant. Cimetidine pretreatment decreased PX plasma clearance by 30%. Metabolic partial clearances to 1-MX + 1-MU and to AFMU were reduced to a similar extent (ca. 40%) in the cimetidine treatment phase, but other pathways were not significantly affected. These data are consistent with 1-MX and AFMU being derived from a common intermediate, the formation of which is mediated by cytochrome P-450. Xanthine oxidase catalyzes only the secondary conversion of 1-MX to 1-MU.