Comparative metabolic disposition of [1-Me14C]caffeine in rats, mice, and Chinese hamsters.
The metabolic disposition of [1-Me14C]caffeine has been studied and compared in three male rodent species: the rat, the mouse, and the Chinese hamster. No interspecies differences appeared in urinary and fecal excretion of radioactivity. However, 1-methyldemethylation was significantly more important in the rat with 20.6 +/- 0.8% of the dose recovered as 14CO2 compared with the Chinese hamster, 16.1 +/- 2%, and the mouse, 13.9 +/- 0.9%. HPLC and TLC analysis of 1-methyl-labeled metabolites showed that the rat exhibits a significantly higher urinary excretion of the four trimethyl derivatives: caffeine, 1,3,7-trimethyluric acid, trimethylallantoin, and 6-amino-5-[N-formylmethylamino]-1,3-dimethyluracil [40.8% of total urine radioactivity) when compared with the Chinese hamster (21.1%) and the mouse (19.7%). Compared with man (6%), these rodents have a greater ability to excrete caffeine without any demethylation. The rat was also characterized by a higher excretion of theophylline while the Chinese hamster excreted more paraxanthine, 1-methylxanthine, and the uracil derivative of paraxanthine. In the mouse, in addition to 1-methylxanthine and 1-methyluric acid, higher amounts of 1,3- and 1,7-dimethyluric acid were found. The mouse was particularly characterized by the presence of an unknown polar metabolite amounting to 22 +/- 3% of urine radioactivity. This metabolite must be produced from paraxanthine because its quantitative formation was inversely related to the excretion of paraxanthine and its metabolites. The observations that this metabolite is neither 5-acetylamino-6-amino-3-methyluracil nor 5-acetylamino-6-formylamino-3-methyluracil reported in humans demonstrate that both quantitative and qualitative interspecies differences occur for caffeine metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
Arnaud
M J
MJ
D000818:Animals; D001345:Autoradiography; D001711:Biotransformation; D001944:Breath Tests; D002110:Caffeine / Q000378:metabolism* / Q000652:urine; D002250:Carbon Radioisotopes; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D006224:Cricetinae; D003412:Cricetulus; D003640:Dealkylation; D008297:Male; D051379:Mice; D051381:Rats; D011919:Rats, Inbred Strains; D013045:Species Specificity; D013806:Theophylline / Q000378:metabolism; D014018:Tissue Distribution
D002250:Carbon Radioisotopes; D002110:Caffeine; D013806:Theophylline; C021183:1,7-dimethylxanthine