Caffeine Use in Sports, Pharmacokinetics in Man, and Cellular Mechanisms of Action

Caffeine is the most widely consumed psychoactive ‘drug’ in the world and probably one of the most commonly used stimulants in sports. This is not surprising, since it is one of the few ergogenic aids with documented efficiency and minimal side effects. Caffeine is rapidly and completely absorbed by the gastrointestinal tract and is readily distributed throughout all tissues of the body. Peak plasma concentrations after normal consumption are usually around 50 μM, and half-lives for elimination range between 2.5–10 h. The parent compound is extensively metabolized in the liver microsomes to more than 25 derivatives, while considerably less than 5% of the ingested dose is excreted unchanged in the urine. There is, however, considerable inter-individual variability in the handling of caffeine by the body, due to both environmental and genetic factors. Evidence from in vitro studies provides a wealth of different cellular actions that could potentially contribute to the observed effects of caffeine in humans in vivo. These include potentiation of muscle contractility via induction of sarcoplasmic reticulum calcium release, inhibition of phosphodiesterase isoenzymes and concomitant cyclic monophosphate accumulation, inhibition of glycogen phosphorylase enzymes in liver and muscle, non-selective adenosine receptor antagonism, stimulation of the cellular membrane sodium/potassium pump, impairment of phosphoinositide metabolism, as well as other, less thoroughly characterized actions. Not all, however, seem to account for the observed effects in vivo, although a variable degree of contribution cannot be readily discounted on the basis of experimental data. The most physiologically relevant mechanism of action is probably the blockade of adenosine receptors, but evidence suggests that, at least under certain conditions, other biochemical mechanisms may also be operational.

Keywords:

• caffeine
• in vitro
• metabolism
• pharmacokinetics
• xanthines

Notes

^aPotencies for agonists and antagonists are given in EC₅₀ and K_b values, respectively, in μM (means and 95% confidence intervals).

^bG-protein types and effects of G coupling have been derived from several cellular systems. Abbreviations used: DAG is diacylglycerol; cAMP is cyclic adenosine 3′,5′-monophosphate; IP₃ is inositol 1,4,5-trisphosphate; PEtOH is phosphatidylethanolamine; PLA₂ is phospholipase A₂; PLC is phospholipase C; PLD is phospholipase D.

^cReceptor protein and corresponding mRNA are often colocalized for the adenosine A₁ and A_2A receptor expression data, but tissue expression of adenosine A_2B and A₃ receptors is mainly based on mRNA distribution alone.

^dPhysiological tissue functions of adenosine A₁, A_2A and A₃ receptors have been confirmed in knockout mouse.