Caffeine metabolism occurs mainly in the liver via the cytochrome CYP1A2 enzyme. The products of caffeine metabolism include paraxanthine, theobromine, and theophylline. The first step of caffeine metabolism is demethylation, yielding paraxanthine (a major metabolite), followed by theobromine, and theophylline, which are both minor metabolites. They are then excreted in urine as urates after additional metabolism. The enzymes xanthine oxidase and N-acetyltransferase 2 (NAT2) also participate in the metabolism of caffeine.
Caffeine is metabolized by the cytochrome P-450 (CYP) enzyme system, principally by isoenzyme 1A2. Therefore, caffeine has the potential to interact with drugs that are metabolized by CYP1A2 or with drugs that induce or inhibit this isoenzyme.
In-vivo and in-vitro experiments showed a progressive increase in the activity of the hepatic microsomal enzymes that metabolize caffeine during neonatal development. In beagle puppies, change in caffeine clearance was determined by the rate of maturation of caffeine-7-demethylase. Caffeine is eliminated in animals by biotransformation in the liver to dimethylxanthines, dimethyl- and monomethyluric acids and uracil derivatives; important quantitative differences have been demonstrated in the formation and elimination of metabolites in rats, mice and Chinese hamsters. These differences are even more important in monkeys, where caffeine is almost completely metabolized to theophylline. ... Some species-dependent metabolites have been identified. Trimethylallantoin was first reported in rats. A ... derivative of paraxanthine was found in mice and identified as the 3-beta-D-glucuronide of paraxanthine. Methylated ureas and sulfur-containing derivatives found in urine in trace amounts are produced by the intestinal flora. In contrast, the acetylated uracil derivative, 5-acetylamino-6-formylamino-3-methyluracil, one of the most important caffeine metabolites in humans, has not been identified in rodents or other animal species. Other uracil derivatives produced from caffeine, theobromine and paraxanthine in rats were found in human urine. In rats, the hepatic demethylation of caffeine shows an age-related decline, resulting in a greatly increased elimination half-time in older adult rats.
Caffeine stimulates medullary, vagal, vasomotor, and respiratory centers, promoting bradycardia, vasoconstriction, and increased respiratory rate. This action was previously believed to be due primarily to increased intracellular cyclic 3′,5′-adenosine monophosphate (cyclic AMP) following inhibition of phosphodiesterase, the enzyme that degrades cyclic AMP. It is now thought that xanthines such as caffeine act as antagonists at adenosine-receptors within the plasma membrane of virtually every cell. As adenosine acts as an autocoid, inhibiting the release of neurotransmitters from presynaptic sites but augmenting the actions of norepinephrine or angiotensin, antagonism of adenosine receptors promotes neurotransmitter release. This explains the stimulatory effects of caffeine. Blockade of the adenosine A1 receptor in the heart leads to the accelerated, pronounced "pounding" of the heart upon caffeine intake.
Some degree of caffeine intake is almost universal in modern society and an estimated 90% of adults in the United States consume caffeine daily, the average amount being 200 mg daily. Yet despite its widescale use, there is no evidence that regular consumption of caffeine or coffee has adverse effects on the liver. Indeed, epidemiological studies suggest that regular coffee intake may have modest protective effects against the progression of chronic liver disease and development of liver cancer. In high, toxic doses, caffeine can have severe effects on brain, heart and muscle function but has not been linked to clinically apparent liver injury. In contrast, there have been several reports of liver injury linked to use of caffeine rich energy drinks. These reports have not been very convincing and most were not well documented. In many instances, the hepatic injury resembled acute hepatic necrosis or ischemic hepatitis (Case 1). In other cases, other diagnoses were more likely than liver injury from the energy drinks (Case 2). Furthermore, it remains unclear whether the hepatic effects were caused by caffeine per se or to other components in typical energy drinks, such as vitamins, herbs or other botanical products. In reports of caffeine overdose including cases with autopsies, hepatic injury has been absent or not mentioned. Thus, caffeine is unlikely to cause liver injury, but the various high caffeine energy drinks which are widely used may possibly cause liver injury when used to excess.
Likelihood score for caffeine: E (unlikely cause of clinically apparent liver injury).
Likelihood score for energy drinks: C[H] (probable rare cause of clinically apparent liver injury when used in high amounts).
Caffeine is rapidly absorbed after oral or parenteral administration, reaching peak plasma concentration within 30 minutes to 2 hours after administration. After oral administration, onset of action takes place within 45 to 1 hour. Food may delay caffeine absorption. The peak plasma level for caffeine ranges from 6-10mg/L. The absolute bioavailability is unavailable in neonates, but reaches about 100% in adults.
The major metabolites of caffeine can be found excreted in the urine. About 0.5% to 2% of a caffeine dose is found excreted in urine, as it because it is heavily absorbed in the renal tubules.
Caffeine has the ability to rapidly cross the blood-brain barrier. It is water and fat soluble and distributes throughout the body. Caffeine concentrations in the cerebrospinal fluid of preterm newborns are similar to the concentrations found in the plasma. The mean volume of distribution of caffeine in infants is 0.8-0.9 L/kg and 0.6 L/kg in the adult population.
World-wide, many fetuses and infants are exposed to methylxanthines via maternal consumption of coffee and other beverages containing these substances. Methylxanthines (caffeine, theophylline and aminophylline) are also commonly used as a medication for apnea of prematurity. ... Methylxanthines readily passes the placenta barrier and enters all tissues and thus may affect the fetus/newborn at any time during pregnancy or postnatal life, given that the effector systems are mature. ...
