Following oral ingestion, caffeine is rapidly and virtually completely absorbed from the gastrointestinal tract into the bloodstream. Mean plasma
Figure 1 Chemical structures of caffeine and the dimethyl-xanthines. (A) Purine ring nomenclature according to E. Fischer; (B) caffeine; (C) theobromine; (D) theophylline; (E) paraxanthine. From Dews (1984).
concentrations of 8-10 mgl-1 are observed following oral or intravenous doses of 5-8mgkg-1. The plasma kinetics of caffeine can be influenced by a number of factors, including the total dose of caffeine, the presence of food in the stomach, and low pH values of drinks, which can modify gastric emptying. Caffeine enters the intracellular tissue water and is found in all body fluids: cerebrospinal fluid, saliva, bile, semen, breast milk, and umbilical cord blood. A higher fraction of the ingested dose of caffeine is recovered in sweat compared to urine. The fraction of caffeine bound to plasma protein varies from 10 to 30%.
There is no blood-brain barrier and no placental barrier limiting the passage of caffeine through tissues. Therefore, from mother to fetus and to the embryo, an equilibrium can be continuously maintained.
The elimination of caffeine is impaired in neonates because of their immature metabolizing hepatic enzyme systems. For example, plasma half-lives of 65-103 h in neonates have been reported compared to 3-6 h in adults and the elderly.
Gender, exercise, and thermal stress have no effect on caffeine pharmacokinetics in men and women. Cigarette smoking increases the elimination of caffeine, whereas decreases have been observed during late pregnancy or with the use of oral contraceptives and in patients with liver diseases. Drug interactions leading to impaired caffeine elimination are frequently reported.
There is no accumulation of caffeine or its metabolites in the body and less than 2% of caffeine is excreted unchanged in the urine. Some rate-limiting steps in caffeine metabolism, particularly demethy-lation into paraxanthine that is selectively catalyzed by CYP1A2, determine the rate of caffeine clearance and the dose-dependent pharmacoki-netics in humans.
Important kinetic differences and variations in the quantitative as well as qualitative metabolic profiles have been shown between species, thus making extrapolation from one species to another very difficult. All of the metabolic transformations include multiple and separate pathways with demethylation to dimethyl- and monomethylxanthines, formation of dimethyl- and monomethylurates, and ring opening yielding substituted diaminouracils (Figure 2). The reverse biotransformation of theophylline to caffeine is demonstrated not only in infants but also in adults.
From metabolic studies, an isotopic caffeine breath test has been developed that detects impaired liver function using the quantitative formation of labeled carbon dioxide as an index. From the urinary excretion of an acetylated uracil metabolite, human acet-ylator phenotype can be easily identified and the analysis of the ratio of the urinary concentrations of other metabolites represents a sensitive test to determine the hepatic enzymatic activities of xanthine oxidase and microsomal 3-methyl demethylation, 7-methyl demethylation, and 8-hydroxylation. Quantitative analyses of paraxanthine urinary metabolites may be used as a biomarker of caffeine intake. Fecal excretion is a minor elimination route, with recovery of only 2-5% of the ingested dose.
Figure 2 Metabolic pathways of caffeine in the human (-the rat (_ __-g.) and the mouse (----t-). From Garattini (1993).
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