Article Figures & Data
Figures
- Fig. 1.
Main pathways and enzymes involved in caffeine degradation. The orange color was used, starting with the first step of caffeine degradation, for the metabolic pathways concerning theophylline and theobromine, while the green color was used for paraxanthine, which is the main metabolite of caffeine and has powerful biological effects. The numbers indicate the percentages of metabolites obtained after caffeine metabolism. AAMU, 5-acetylamino-6-amino-3-methyluracil; AFMU, 5-acetylamino-6-formylamino-3-methyluracil; CYP, cytochrome P450 followed by the number corresponding to each specific isoform; NAT2, N-acetyltransferase-2; XO, xanthine oxidase.
Tables
- TABLE 1
Benefits and risks of exposure to caffeine
Data according to Kawachi et al. (1996), Ferré (2008), Goldstein et al. (2010), Nehlig (2010), Lucas et al. (2011), Caldeira et al. (2013), Derry et al. (2014), Panza et al. (2015), Doepker et al. (2016), Zuchinali et al. (2016), Grosso et al. (2017).
System Benefit Risk Lack of Effect Central nervous system Increased alertness Sleep disturbances Better attention Nervousness Increased concentration Jitteriness Increased focus Irritability Increased energy Anxiety Improved cognition Decreased reaction time Reduction of cognitive failures (improvement of driving performance, reduction of accidents at work) Improved productivity at work Reduced fatigue Improved mood Feeling of well-being Headache relief Prevention of age-related cognitive decline Prevention of Alzheimer disease Prevention of Parkinson disease Cardiovascular system Protection against stroke Slight blood pressure increases among regular drinkers No increased risk of total cardiovascular disease No effect on arrhythmias even in patients at risk No increased risk of atrial fibrillation No increased risk of heart failure No hypertension among regular drinkers in baseline populations Sports activities Improvement in team and power-based sports, sustained maximal endurance, resistance and time-trial performance No effect in short-term sports activities Retardation of exhaustion feeling - TABLE 2
Drugs that influence caffeine pharmacokinetics
Data according to Soto et al. (1994), Amchin et al. (1999), Schmider et al. (1999), Carrillo and Benitez (2000 and references therein), Granfors et al. (2004), Culm-Merdek et al. (2005), Backman et al. (2006), Cysneiros et al. (2007), Darwish et al. (2008), Dinger et al. (2016), Yamazachi et al. (2017).
Drug Class Name Effect on Caffeine Half-Life Oral contraceptives All About +40% Quinolone antibiotics Ami- and difloxacin +21% Ciproflacin +70% Enoxacin +75% Fleroxacin No effect Grepafloxacin +50% Lomeflaxin +23% Nalidixic acid +67% Norfloxacin +35% Ofloxacin No effect Pefloxacin +22–47% Pipemidic acid +59% Rufloxacin No effect Temafloxacin No effect Tosufloxacin +34% Trovafloxacin No effect Cardiovascular drugs Mexiletine (anti-arrhythmic) +30%–50% Diltiazem (calcium antagonist) +22% Verapamil (calcium antagonist) +20% Propafenone (anti-arrhythmic) Increase Propranolol (beta-blocker) Increase Triamterene (diuretic) Increase Warfarin (anticoagulant) Increase CNS drugs Clozapine (antidepressant) Variable, up to +26% Fluvoxamine (antidepressant) −80%; decreases caffeine half-life by sixfold Venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor (SNRI) No significant effect Alprazolam (anti-anxiety) No significant effect Olanzapine (antipsychotic) (Shirley et al. 2003) Slows clearance, interindividual variability Tryptamine derivatives (psychoactive) Slows caffeine clearance to various degrees Armodafinil (wakefulness promoting) No significant effect Tacrine (cholinesterase inhibitor) Slows slightly clearance Zolpidem (Hypnotic) No significant effect Anti-inflammatory drugs Idrocilamide Half-life increased up to 63 h Rofecoxib Decreased clearance Antifungal medication Fluconazole + 25% Isavuconazole No effect Ketoconazole + 11% Terbinafine + 21% Proton pump inhibitors Cimetidine −31% Lansoprazole No effect Omeprazole −41% Pantoprazole No effect Ondansetron (anti-vomiting) Slows clearance Psoralens, anti-psoriasis and anti-eczema drugs Methoxsalen −70% 5-Methoxypsoralen −31% Bronchodilators Furafylline Increases caffeine half-life up to 10-fold Theophylline Slows caffeine clearance, twofold - TABLE 3
Interactions between caffeine and antiepileptic drugs (AEDs)
Data according to Czuczwar et al. (1990), Wlaz et al. (1992), Gasior et al. (1996, 1998), Vaz et al. (1998), Zuchora et al. (2005), Luszczki et al. (2006), Jankiewicz et al. (2007), Chrościńska-Krawczyk et al. (2009, 2016), Walzer et al. (2012).
Anticonvulsant Species Type of Interaction Classic AEDs Carbamazepine Rats, mice Acute and chronic caffeine dose-dependently decrease efficacy Carbamazepine Humans Increases half-life by twofold; decreases bioavailability by 32% Clobazam Humans No significant action on clobazam pharmacokinetics No interactions between clobazam and valproate or lamotrigine Clonazepam Rats No significant effect Diazepam Mice Decrease in efficacy Diphenylhydantoin Mice Decrease in efficacy Ethosuximide Rats Decrease in efficacy Phenobarbital Rats No significant effect Mice Decrease in efficacy Phenytoin Mice Decrease in efficacy Valproate Rats No significant effect Mice Decrease in efficacy Second generation AEDs Felbamate Mice No significant effect, decreased efficacy only at very high doses (100–160 mg/kg caffeine) Gabapentin Mice Decrease in efficacy Lamotrigine Mice No significant interaction Oxcarbazepine Mice No significant interaction Tiagabine Mice No significant interaction Topiramate Mice Decrease in efficacy - TABLE 4
Pharmacokinetic regulation of caffeine consumption linked to genetic polymorphism
More details can be found in the text.
Enzyme Biologic Role Clinical Relevance Replication Location in Text CYP1A1 CYP1A1 metabolizes Association with habitual caffeine consumption Yes IV.A.4 – caffeine to paraxanthine, theobromine and 1,3,7-TMU – polycyclic aromatic hydrocarbons, which are important constituents of coffee CYP1A2 Major enzyme involved in liver caffeine metabolism Association with habitual caffeine consumption Yes IV.A.1 IV.A.4 CYP2A6 Metabolism of paraxanthine to 1,7-DMU No clear link with consumption shown yet Yes IV.A.1 NAT2 Metabolism of paraxanthine to AFMU No clear link with consumption shown yet Yes IV.A.2 XO Metabolism of 1-MX to 1-MU 1MU:1MX ratio used following caffeine administration as a pharmacodynamic measure of drug effect on XO activity Yes IV.A.3 AFMU, 5-acetylamino-6-formylamino-3-methyluracil; CYP, cytochrome P450 followed by the number corresponding to each specific isoform; NAT2, N-acetyltransferase-2; XO, xanthine oxidase; 1,3,7-TMU, 1,3,7-trimethyluric acid; 1,7-DMU, 1,7-dimethyluric acid; 1-MX, 1-methylxanthine; 1-MU, 1-methyluric acid.
- TABLE 5
Potential role of the polymorphisms of ADORA2A and adenosine deaminase genes in caffeine-related functions and caffeine consumption
More details can be found in the text.
Gene Biologic Role Clinical Relevance Replication Location in Text ADORA2A Anxiety Modulation of anxiety levels in response to caffeine intake Yes IV.B.1.a Attention Influence on attentional processing and working memory Yes IV.B.1.a Emotional processing Influence on startle reflex Yes IV.B.1.a Maladaptive emotional processing Impact on the selection of relevant early information Panic disorder Extreme reactions to stressful situations Yes IV.B.1.a Agoraphobia Sleep Susceptibility to hyperarousal-induced insomnia Yes IV.B.1.b Sleep latency Modification of EEG sleep-linked characteristics Caffeine consumption Carrying the 1976TT genotype decreases caffeine consumption No IV.B.1.c Adenosine deaminase Sleep Role in sleep architecture and maintenance Yes IV.B.1.b Controls the frequency of awakenings
In this issue
Variation in Caffeine Metabolism
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- Article
- Abstract
- I. Introduction
- II. Caffeine Metabolism and Pharmacokinetics
- III. Effect of Various Factors on Caffeine Metabolism
- IV. The Role of Tolerance in the Variability of Caffeine Consumption
- V. Interindividual Differences Due to Genetic Factors
- VI. Conclusion
- Authorship Contributions
- Footnotes
- Abbreviations
- References
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