A study on the route of 1-methylurate formation in theophylline metabolism

Abstract

The urinary excretion patterns of theophylline metabolites were studied in a subject on a routine, oral dose of 600 mg/day. The highest correlation was observed between the excretions of 1,3-dimethylurate and 1-methylurate (r = 0.73 +/- 0.08). The poorest correlations were observed when the excretion of 1-methylxanthine was compared to those of 1-methylurate and 1,3-dimethylurate (r < or = 0.55, P > or = 0.05). The difference in the quality of the correlations was not due to rate-limiting or class-specific carries. The results suggested that 1-methylurate did not derive solely from 1-methylxanthine, implicating 1,3-dimethylurate as an alternative source. When the theophylline regimen was supplemented by a single dose of caffeine (4.80 mg/kg), the recovery of unaltered caffeine and the yield of metabolites arising from the primary 3-demethylation of caffeine (1-methylxanthine, 7-methylxanthine, 1-methylurate, 1,7-dimethylxanthine and 1,7-dimethylurate) were found to be unchanged. The lack of competition between caffeine and theophylline indicated that caffeine 3-demethylation and the demethylations of theophylline are not catalyzed by the same cytochrome P450 system.

Genome-Wide Association Study with Targeted and Non-targeted NMR Metabolomics Identifies 15 Novel Loci of Urinary Human Metabolic Individuality

“…For 5 of the 14 loci, we considered the associated metabolic traits in blood and urine to be biochemically related. Here, the metabolites are either products of the enzyme coded by the candidate gene ( NAT8 : N-acetylated compounds), or they are linked through an enzymatic reaction other than the reaction catalyzed by the candidate gene’s product ( NAT2 : 1,3-dimethylurate and 1-methylurate [ 73 ]; PYROXD2 : trimethylamine and dimethylamine [EC 1.5.8.2]; SLC7A9 : lysine and homocitrulline [EC 2.1.3.8]), or they belong to the same metabolite class ( TKT : gluconate and erythronate are aldonates). The observed associations of related but different metabolites in blood and urine may be indicative either for biochemical conversions before excretion, or simply be a result of differences in the composition of the metabolite panels covered by the various mGWAS.…”

Untargeted metabolomics for uncovering biological markers of human skeletal muscle ageing

“…1,7/3,7-dimethylurate is another metabolite of nucleotide metabolism associated with the purine xanthine. It is also known as a breakdown product and marker of the pharmacokinetics of the COPD and asthma drug Theophylline or Dimethylxanthine [ 74 ], and in the metabolism of caffeine [ 75 ]. Interestingly the isomer 1,7 dimethylurate in plasma has been shown to be related to chronological ageing in previous untargeted metabolomics studies [ 32 ].…”