The fact that the human body converts 70–80 percent of caffeine into paraxanthine with no apparent toxic effects following caffeine doses of 300–500 mg/day suggests that paraxanthine's toxicological potency is low. Caffeine is cleared more quickly than paraxanthine, so 8 to 10 hours after caffeine ingestion, paraxanthine levels exceed caffeine levels in plasma (Arnaud, 1993). Paraxanthine is the dominant metabolite in humans, rising in plasma to concentrations 10 times those of theophylline or theobromine. This first metabolic step accounts for approximately 75–80 percent of caffeine metabolism and involves cytochrome P4501A2 (Arnaud, 1993). In humans 3-ethyl demethylation to paraxanthine is the primary route of metabolism (Arnaud, 1987). It is metabolized in the liver to dimethylxanthines, uric acids, di- and trimethylallantoin, and uracil derivatives. In healthy humans, repeated caffeine ingestion does not alter its absorption or metabolism (George et al., 1986). Caffeine metabolism occurs primarily in the liver, catalyzed by hepatic microsomal enzyme systems (Grant et al., 1987). Its limited appearance in urine indicates that caffeine metabolism is the rate-limiting factor in its plasma clearance (Arnaud, 1993). In a study of adult men, a dose of 4 mg/kg (280 mg/70 kg human, or about 2–3 cups of coffee) had a caffeine half-life of 2.5–4.5 hours, and was not affected by age (Arnaud, 1988).īecause 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 elimination is by first-order kinetics and is adequately described by a one-compartment open model system (Bonati et al., 1982). However, caffeine is also sufficiently lipophilic to pass through all biological membranes and readily crosses the blood-brain barrier. The distribution volume within the body is 0.7 L/kg, a value suggesting that it is hydrophilic and distributes freely into the intracellular tissue water (Arnaud, 1987, 1993). Caffeine binds reversibly to plasma proteins, and protein-bound caffeine accounts for about 10 to 30 percent of the total plasma pool. Once caffeine is absorbed, there appears to be no hepatic first-pass effect (i.e., the liver does not appear to remove caffeine as it passes from the gut to the general circulation), as evidenced by the similarity in plasma concentration curves that follow its administration by either the oral or the intravenous route (Arnaud, 1993). This wide variation in time may be due to variation in gastric emptying time and the presence of other dietary constituents, such as fiber (Arnaud, 1987). Peak plasma concentrations occur between 15 and 120 minutes after oral ingestion. More rapid absorption can be achieved by chewing caffeine-containing gum or other preparations that allow absorption through the oral mucosa. When it is consumed in beverages (most commonly coffee, tea, or soft drinks) caffeine is absorbed rapidly from the gastrointestinal tract and distributed throughout body water. These effects include mild CNS stimulation and wakefulness, ability to sustain intellectual activity, and decreased reaction times.Ĭaffeine is rapidly and completely absorbed in humans, with 99 percent being absorbed within 45 minutes of ingestion (Bonati et al., 1982 Liguori et al., 1997). The pharmacological effects of caffeine are similar to those of other methylxanthines (including those found in various teas and chocolates). This wide range in the plasma mean half-life of caffeine is due to both innate individual variation, and a variety of physiological and environmental characteristics that influence caffeine metabolism (e.g., pregnancy, obesity, use of oral contraceptives, smoking, altitude). However, caffeine's elimination half-life may range between 1.5 and 9.5 hours, while the total plasma clearance rate for caffeine is estimated to be 0.078 L/h/kg (Brachtel and Richter, 1992 Busto et al., 1989). The mean half-life of caffeine in plasma of healthy individuals is about 5 hours. Structurally, caffeine (and the other methylxanthines) resembles the purines. In pure form, it is a bitter white powder.

This chapter provides a brief summary of the metabolism and physiological effects of caffeineĬaffeine (1,3,7-trimethylxanthine) is a plant alkaloid with a chemical structure of C 8H 10N 4O 2 (see Figure 2–1) and a molecular weight of 194.19. It has numerous pharmacological and physiological effects, including cardiovascular, respiratory, renal, and smooth muscle effects, as well as effects on mood, memory, alertness, and physical and cognitive performance. As stated in Chapter 1, caffeine is the most widely used central nervous system (CNS) stimulant in the world.

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