Caffeine and metabolism

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Factors including smoking status, liver disease, alcohol consumption, some medications, and diet may all influence caffeine’s effect on an individual, with data suggesting that genetics also play a critical role, not only in how an individual reacts to caffeine, but in determining how much coffee they are likely to drink in the first place16,17.

Studies have investigated the different factors that influence how the body metabolises caffeine and how caffeine intake affects everyday activity16,17.

Caffeine in the body

Following oral consumption, caffeine is absorbed into the blood and body tissues. Absorption is virtually complete about 45 minutes after ingestion7. The peak plasma caffeine concentration is reached 15-120 minutes after ingestion. Caffeine has a half-life of approximately four hours, although this timescale may be reduced or extended in certain groups of individuals such as pregnant women, those who smoke and people with impaired liver function16,17.

Caffeine’s effects will last for several hours, depending on how quickly or slowly it is metabolised by the body7.

Caffeine absorption from food and beverages does not seem to depend on age, gender, genetic background, and disease or drugs, alcohol and nicotine consumption. Caffeine absorption from tea and coffee is similar18.

How the body metabolises caffeine

Caffeine is primarily metabolised in the liver by cytochrome P450 enzymes, which are responsible for more than 90% of caffeine clearance19. The enzyme responsible for metabolism of caffeine is coded for by the gene CYP1A2.

The large variability of CYP1A2 activity influences the clearance of caffeine and may be affected by factors such as gender, race, genetic polymorphisms, disease, and exposure to inducers16,17,19. Two studies have reported that regular intakes of caffeine for one week did not alter caffeine pharmacokinetics20,21. However, a further study suggested that the daily consumption of at least 3 cups of coffee increased CYP1A2 activity22.

Caffeine, health and individual factors

A number of individual, non-genetic factors can impact the way caffeine is metabolised and utilised in the body.

Liver disease

The liver is the main organ responsible for caffeine metabolism. A small number of studies have looked at the potential impact of certain types of liver disease including cirrhosis and hepatitis B or C, suggesting that they may cause a reduction of plasma clearance of caffeine in correlation with the severity of the disease23,24. (See Liver Function topic for more information)

Smoking status

Research suggests that smoking stimulates caffeine clearance16, and almost doubles the rate of caffeine metabolism as a result of enzyme induction25,26.

Cessation of smoking reduces caffeine clearance and changes the pattern of caffeine metabolism back to normal27.

Diet

A number of dietary factors may also affect caffeine metabolism.

Grapefruit juice consumption decreases caffeine clearance by 23% and prolongs half-life by 31%28,29.

Consumption of broccoli and brassica vegetables in general30 and absorption of large quantities of vitamin C increase caffeine clearance31.

The flavonoid, quercetin, found widely in fruit and vegetables, affects the metabolism of caffeine and paraxanthine and mainly decreases the urinary excretion of the latter compound by 32%; it also changes the excretion of several other metabolites of caffeine32.

Women’s health

During pregnancy, caffeine metabolism is reduced, particularly during the third trimester33,34. This is associated with a reduction in the activity of the main enzyme involved in caffeine metabolism, and a consequent increase in caffeine half-life35.  Caffeine metabolism returns to normal a few weeks after delivery35.

The European Food Safety Authority (EFSA) advises that pregnant women limit their caffeine intake to 200mg from all sources4.

The use of oral contraceptives almost doubles caffeine half-life, mainly during the second half of the menstrual cycle (the luteal phase)35.

Alcohol intake

Alcohol has an inhibitory effect on CYP1A2 activity (the enzyme involved in caffeine clearance)36. Alcohol intake of 50g per day prolongs caffeine half-life by 72% and decreases caffeine clearance by 36%20.

Caffeine does not modify the motor or psychological symptoms of alcoholic intoxication37 nor does it cancel out the negative effects of alcohol on driving abilities despite its effects on vigilance and reaction time38,39.

Some medications

Caffeine pharmacokinetics may be modified by some medical drugs. Therefore, when prescribing caffeine-containing medicine or medicines that interact with caffeine metabolism, healthcare professionals should consider whether dosage adjustments or specific advice on caffeine consumption are required16.

Genetic variability

Genetics may play a role in determining whether a person experiences side effects from caffeine16,17.

Genetic variability in caffeine receptors

ADORA2A polymorphism

Adenosine A2 receptors are key to the stimulating effect of caffeine (see Mental Performance for further information). Human studies have shown that polymorphisms of these receptors may have an effect on the body16,17.

Research suggests that the probability of having the ADORA2A genotype decreases as habitual caffeine consumption increases, meaning that individuals with this genotype may be less sensitive to the effects of caffeine and therefore be more likely to choose caffeinated beverages16,17,40.

  • A 2012 study considered the variability in the effect of caffeine intake on blood pressure (BP), suggesting that the variability in the acute BP response to coffee may be partly explained by genetic polymorphisms of the adenosine A2A receptors and α2-adrenergic receptors41.
  • A large consortium (PEGASUS) study combined data from five population-based case-control studies including 1,325 Parkinson’s Disease (PD) cases and 1,735 controls. The study reported that PD risk was inversely associated with two ADORA2 polymorphisms42.
  • The distribution of distinct genotypes of the adenosine A2A receptor gene (ADORA2A) differs between self-rated caffeine-sensitive individuals with reduced sleep quality, and caffeine-insensitive individuals40. The same amount of caffeine can therefore affect two otherwise similar individuals differently, depending on their genetic make-up.

Genetic variability in metabolism – CYP1A2 polymorphism

A polymorphism of the gene coding for CYP1A2, the enzyme responsible for 95% of caffeine metabolism, may potentially divide the population into ‘slow’ and ‘fast’ caffeine metabolisers16,17.

A meta-analysis looked at the association between habitual coffee intake and CYP1A2 polymorphism that splits the population into fast caffeine metabolisers and slow caffeine metabolisers43. The analysis showed an association between fast metabolisers and coffee consumption in males, individuals younger than 59 years, and Caucasians, but not in females, individuals older than 59 years, and Asians. This is the first study to identify a weak association between the fast caffeine metaboliser profile and coffee intake in the Asian population as well as the age and gender related variation. Further research will support our understanding43.

Caffeine intakes

The ADORA2A genotype is associated with different amounts of caffeine intake. Individuals with the ADORA2A 1976TT genotype are significantly more likely to consume less caffeine44.

Since individual reactions to caffeine may differ according to genetic variability, individuals tend to only consume the amount of caffeine they feel comfortable with44.

The European Food Safety Authority (EFSA) advises that daily caffeine intakes of up to 400mg and single doses of up to 200mg do not raise concerns when consumed as part of a health balanced diet4. 400mg caffeine is equivalent to up to 5 cups of coffee per day, as part of a healthy balanced diet and an active lifestyle. EFSA recommends lower levels for pregnant women, who are advised to limit caffeine intake to 200mg from all sources4.

Potential further research

Further research into caffeine could categorise populations by gene-type  consider the impact of caffeine consumption on various functions. A better understanding of the factors influencing caffeine intake could help to identify critical factors affecting quality of life and/or susceptibility to disease16,17.

This information is intended for Healthcare professional audiences.
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