>>13853262https://www.ncbi.nlm.nih.gov/books/NBK223808/Because caffeine is readily reabsorbed by the renal tubules, once it is filtered by the glomeruli only a small percentage is excreted unchanged in the urine. Its limited appearance in urine indicates that caffeine metabolism is the rate-limiting factor in its plasma clearance (Arnaud, 1993). Caffeine metabolism occurs primarily in the liver, catalyzed by hepatic microsomal enzyme systems (Grant et al., 1987). In healthy humans, repeated caffeine ingestion does not alter its absorption or metabolism (George et al., 1986). It is metabolized in the liver to dimethylxanthines, uric acids, di- and trimethylallantoin, and uracil derivatives. In humans 3-ethyl demethylation to paraxanthine is the primary route of metabolism (Arnaud, 1987). This first metabolic step accounts for approximately 75–80 percent of caffeine metabolism and involves cytochrome P4501A2 (Arnaud, 1993). Paraxanthine is the dominant metabolite in humans, rising in plasma to concentrations 10 times those of theophylline or theobromine. Caffeine is cleared more quickly than paraxanthine, so 8 to 10 hours after caffeine ingestion, paraxanthine levels exceed caffeine levels in plasma (Arnaud, 1993).
