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Data on toxicokinetics, absorption, distribution, metabolism, and excretion of caffeine have been well summarized in reviews/review-like-publications of good reliability Arnaud, 1993; IARC, 1991). However; it cannot be stated whether the studies/results cited in these publications and listed herein do satisfy the requirements of current guidelines.

 

METABOLISM

The main urinary metabolites of caffeine in humans are 1-methyluric acid, 1-methylxanthine, and 1,7-dimethyluric acid.

The main urinary metabolites of caffeine in rats and mice are 1,3-dimethyluracil, paraxanthine, trimethyluric acid, theophylline, and theobromine.

Caffeine metabolism is qualitatively relatively similar in animals and humans. The main metabolic pathways are demethylation and hydroxylation of the 8-position leading to the formation of the respective uracil and uric acid derivatives. There are, however, some quantitative differences in the metabolic profile:

  • Humans are characterized by the importance of 3-methyl demethylation leading to the formation of paraxanthine and especially metabolites thereof through subsequent metabolic steps. The main urinary metabolites in humans are 1-methyluric acid, 1-methylxanthine, and 1,7-dimethyluric acid. 
  • In rats and mice, the metabolism of caffeine is predominantly via theobromine and theophylline. The main urinary metabolites are 1,3-dimethyluracil, paraxanthine, trimethyluric acid, theophylline, and theobromine.

Caffeine metabolism decreases during pregnancy, resulting in higher serum concentrations.

Caffeine absorption and distribution from gastrointestinal tract is rapid and complete and it is distributed to all body fluids and appeared in all tissues within 5 minutes.

There is no accumulation of caffeine or its metabolites in any organ even after high doses.

No blood-brain barrier or placental barrier was detected.

The fraction bound to plasma albumin varies from 10 to 30%.

Caffeine is metabolized by liver microsomal mixed-function oxidases and can increase metabolizing enzymes at high doses (75 mg/kg).

 

EXCRETION / ELIMINATION

In both humans and rats, excretion of caffeine mainly occurs via urine (about 90% dose in rats; > 95% in humans).

It is eliminated by various species by first-order kinetics, described by a one-compartment open model system.

The half-life for several species ranged between 0.7 to 12 h (rats to baboons) and a mean volume of distribution of 0.8 l/kg has been reported for various species. Decreased as well as increased half-lives were found in pregnant animals.

Caffeine is eliminated in animals by biotransformation to dimethylxanthines, dimethyl- and monomethyluric acids and uracil derivatives. Differences in formation and elimination of metabolites were noted in rats, mice and Chinese hamsters and mainly in monkeys, where it is almost completely metabolized to theophylline. In contrast, the acetylated uracil derivative, 5-acetylamino-6-formylamino-3-methyluracil, one of the most important metabolites in human, was not found in rodents or other species.

DEMRMAL ABSORPTION

In vitro percutaneous absorption of caffeine through human and rat skin was investigated in the study of van de Sandt et al., 2004. The maximum absorption rate through rat skin (6.82µg/cm²/h) was clearly higher than the mean value for human skin (2.24 ± 1.43 µg/cm²/h). The amount in the receptor fluid after 24 h was 24.5 ± 11.6% and53.7 %of the dose applied in human and rat skin, respectively. The total penetration (% of dose) through rat skin (61.3 ± 4.0 %) was also higher than the mean value for human skin (26.75 ± 10.9 %). Skin thickness only slightly influenced the absorption of caffeine.

In conclusion there is a total absorption of the human skin of about 25 %.