II. Consumption and Metabolism of Caffeine
A. Sources of Caffeine
Although coffee and other caffeine-containing beverages were introduced in Europe only a few hundred years ago, consumption of these beverages now occupies a significant place in our national cultures. The same can be said for most nations of the world (see Table
Caffeine is present in a number of dietary sources consumed worldwide, i.e., tea, coffee, cocoa beverages, chocolate bars, and soft drinks. The content of caffeine of these various food items ranges from 40 to 180 mg/150 ml for coffee to 24 to 50 mg/150 ml for tea, 15 to 29 mg/180 ml for cola, 2 to 7 mg/150 ml for cocoa, and 1 to 36 mg/28 g for chocolate (Barone and Roberts, 1996
; Debry 1994; see also Table 2). Difficulties in taking all the sources into account may partly explain the considerable differences, such as in the estimates of caffeine consumption in the United Sates [from 196 to 423 mg/ 24 h; Weidner and Istvan (1985)] or in the UK [from 359 to 621 mg/24 h; Bruce and Lader (1986)].
Caffeine consumption from all sources can be estimated to around 70 to 76 mg/person/day worldwide (Gilbert, 1981, 1984) but reaches 210 to 238 mg/day in the US and Canada and more than 400 mg/person/day in Sweden and Finland, where 80 to 100% of the caffeine intake comes from coffee alone (Debry, 1994; Barone and Roberts, 1996; Viani, 1996). In the UK, the consumption is as high as in Sweden and Finland, but 55% comes from tea, 43% from coffee, and 2% from colas (Barone and Roberts, 1996). According to the recent survey of Barone and Roberts (1996), the daily intake of caffeine from all sources in the US is estimated at 3 mg/kg/person, two-thirds of it coming from coffee in subjects more than 10 years old. If only consumers are taken into account, the daily caffeine consumption reaches a value of 2.4 to 4.0 mg/kg (170-300 mg) in a 60- to 70-kg individual. In 7- to 10-year-old children, the daily consumption of caffeine ranges from 0.5 to 1.8 mg/kg. The soft drinks represent 26 to 55%, chocolate foods and beverages 17 to 40%, tea 6 to 34%, and coffee 0 to 22% of the total caffeine intake (Morgan et al., 1982; Arbeit et al., 1988; Ellison et al., 1995). It is also clear from the data given below that the amounts of caffeine ingested via these sources are biologically active. This emphasizes that caffeine is indeed the most widely used of all psychoactive drugs.
B. Caffeine Absorption, Distribution, and Pharmacokinetics
Caffeine absorption from the gastrointestinal tract is rapid and reaches 99% in humans in about 45 min after ingestion (Marks and Kelly, 1973
The hydrophobic properties of caffeine allow its passage through all biological membranes. There is no blood-brain barrier to caffeine in the adult or the fetal animal (Lachance et al., 1983
; Tanaka et al., 1984), and the blood-to-plasma ratio is close to unity (McCall et al., 1982), indicating limited plasma protein binding and free passage into blood cells. In newborn infants, caffeine concentration is similar in plasma and cerebrospinal fluid (Turmen et al., 1979; Somani et al., 1980). There is no placental barrier to caffeine (Ikeda et al., 1982; Kimmel et al., 1984) and unusually high levels of caffeine have been reported in premature infants born to women who are heavy caffeine consumers (Khanna and Somani, 1984). Finally, saliva concentrations of caffeine, which are considered to be a reliable index of plasma caffeine levels, reach 65 to 85% of plasma concentrations (Cook et al., 1976; Khanna et al., 1980).
Peak plasma caffeine concentration is reached between 15 and 120 min after oral ingestion in humans and equals 8 to 10 mg/l for doses of 5 to 8 mg/kg (Arnaud and Welsch, 1982; Bonati et al., 1982). Ingestion of a single cup of coffee provides a dose of 0.4 to 2.5 mg/kg. It can therefore be estimated that this gives a peak concentration of 0.25 to 2 mg/l or approximately 1 to 10 µM.
For doses lower than 10 mg/kg, caffeine half-lives range from 0.7 to 1.2 h in rat and mouse, 3 to 5 h in monkey (Bonati et al., 1984-1985) and 2.5 to 4.5 h in humans (Arnaud, 1987). There are no differences in caffeine half-life in young and elderly humans (Blanchard and Sawers, 1983b). Conversely, caffeine half-life is increased during the neonatal period due to lower activity of cytochrome P-450 (Aranda et al., 1979) and to the relative immaturity of some demethylation and acetylation pathways (Aranda et al., 1974; Carrier et al., 1988). The half-life of caffeine is about 80 ± 23 h for the full-term newborn infant (Aranda et al., 1977; Le Guennec and Billon, 1987) and can be over 100 h in premature infants (Parsons and Neims, 1981). Thereafter, the half-life of caffeine decreases exponentially with postnatal age to 14.4 and 2.6 h in 3- to 5- and 5- to 6-month-old infants, respectively (Aldridge et al., 1979; Parsons and Neims, 1981; Paire et al., 1988; Pearlman et al., 1989). The clearance of caffeine is low in 1-month-old infants (31 ml/kg/h), increases to a maximal value of 331 ml/kg/h at 5 to 6 months, and is 155 ml/kg/h in adult humans (Aranda et al., 1979). In adult males, caffeine half-life is reduced by 30 to 50% in smokers compared with nonsmokers (Hart et al., 1976; Joeres et al., 1988; Murphy et al., 1988), whereas it is approximately doubled in women taking oral contraceptives (Patwardhan et al., 1980) and greatly prolonged (up to 15 h) during the last trimester of pregnancy (Aldridge et al., 1981; Knutti et al., 1981; Brazier et al., 1983).
C. Caffeine Metabolism
Caffeine is metabolized by the liver to form dimethyl- and monomethylxanthines, dimethyl and monomethyl uric acids, trimethyl- and dimethylallantoin, and uracil derivatives (Arnaud, 1987
Some metabolites of caffeine also have marked pharmacological activity. Thus, 1,3-dimethylxanthine (theophylline) and 1,7-dimethylxanthine (paraxanthine) must be taken into account when considering the biological actions of caffeine-containing beverages. In rodents, paraxanthine is the major metabolite in plasma, but levels of theophylline are also high. The metabolism of caffeine to paraxanthine can be used to phenotype individuals with regard to one subform of cytochrome P-450, CYP1A2 (Fuhr et al., 1996
; Miners and Birkett, 1996). By contrast, the formation of theophylline from caffeine does not correlate with any specific subform.
It has recently been shown that, after long-term caffeine ingestion, the levels of theophylline in the mouse brain may be higher than those of caffeine during a substantial part of the day and almost always higher than the levels of paraxanthine (Johansson et al., 1996a). This could mean that caffeine in the brain is metabolized partly via specific, local enzymatic pathways and that caffeine administration leads to high central nervous system (CNS) concentrations of theophylline, whereas peripheral theophylline levels are kept low. It is possibly relevant that demethylation of caffeine to paraxanthine in rats appears to be predominantly catalyzed by cytochrome P-450, whereas demethylation to theophylline and theobromine may also take place via flavin-containing monooxygenases (Chung and Cha, 1997). Future studies will have to be performed to determine if the situation is similar in humans. It is, however, clear that the contention that most of the effects of caffeine in the CNS are direct or indirect consequences of adenosine receptor blockade (see Section III below) increases in strength if local CNS concentrations of theophylline and/or paraxanthine are high after caffeine ingestion. Theophylline is some three to five times more potent than caffeine as an inhibitor of both adenosine A1 and A2A receptors, and paraxanthine is also at least as potent as caffeine. Indeed it has been shown that, in humans, some tested effects of caffeine are readily mimicked by paraxanthine (Benowitz et al., 1995).
Because so much of the background information is derived from animal experiments, we must try to extrapolate the data to humans. However, it is not a trivial task to compare doses of caffeine in animals and humans. For example, it must be kept in mind that in most experiments on rodents, one single high dose of caffeine is administered, whereas human consumption of coffee is divided up during the day. Gilbert (1976) suggested the use of a metabolic body weight correction factor when comparing the effect of a given dose of caffeine in animals and humans. However, not everyone agrees that such a correction based on the metabolic body weight should be applied. Indeed the LD50 of caffeine is fairly consistent across species, including Homo sapiens (Dews, 1982). The plasma level resulting from 1.1 mg/kg caffeine (a single cup of coffee containing 80 mg of caffeine ingested by a 70-kg human) ranges from 0.5 to 1.5 mg/l. A similar dose-concentration relationship is found in many species, including rodents and primates (Hirsh, 1984). However, because the metabolism of caffeine differs between rodents and humans and the half-life of the methylxanthine is much shorter in rats (0.7-1.2 h) than in humans (2.5-4.5 h) (Morgan et al., 1982), it seems reasonable to correct for the metabolic body weight when comparing animal and human doses. Thus, it is generally assumed that 10 mg/kg in a rat represents about 250 mg of caffeine in a human weighing 70 kg (3.5 mg/kg), and that this would correspond to about 2 to 3 cups of coffee.
). The demethylation, C-8 oxidation, and uracil formation occur mostly in liver microsomes. The major metabolic difference between rodents and humans is that, in the rat, 40% of the caffeine metabolites are trimethyl derivatives as compared with less than 6% in humans (Arnaud, 1985
). Metabolism in humans is characterized by the quantitative importance of the 3-methyl demethylation leading to the formation of paraxanthine. This first metabolic step represents up to 72 to 80% of caffeine metabolism (Arnaud and Welsch, 1982
; Arnaud, 1993
). Many of the metabolic steps may be saturable in humans as the elimination half-time for not only caffeine, but also some of its metabolites, is dose-dependent (Kaplan et al., 1997
; Bonati et al., 1982
; Blanchard and Sawers, 1983a
; Arnaud, 1993
). Caffeine absorption is also complete in animals (Arnaud, 1976
). Pharmacokinetics are comparable after oral or i.v. administration of caffeine in humans and animals, leading to superimposable plasma curves (Arnaud, 1993
). Absorption is, however, not complete when the substance is taken as coffee (Morgan et al., 1982
). It is also known that when very large doses of caffeine are accidentally ingested, toxic effects appear, with an LD50
of about 200 mg/kg in rats (see Eichler, 1976
). In patients who have been admitted to hospital due to acute caffeine poisoning, levels of a few hundred micromoles per liter have been recorded.1
). The national consumption of caffeine summarized in this table relies heavily on official statistics, which are notoriously unreliable. It is, for example, possible that the rather low figures for caffeine consumption in countries that produce the relevant plants may partly be due to the fact that not all the production has entered into the official statistics. In addition, Table 1
does not include soft drinks, although they are a major source of caffeine for example for children in Western society.