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Review ArticleReview Article

Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption

Astrid Nehlig
Stephen P. H. Alexander, ASSOCIATE EDITOR
Pharmacological Reviews April 2018, 70 (2) 384-411; DOI: https://doi.org/10.1124/pr.117.014407
Astrid Nehlig
INSERM U 1129, Pediatric Neurology, Necker-Enfants Malades Hospital, University of Paris Descartes, Inserm U1129, Paris, France
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Stephen P. H. Alexander
Roles: ASSOCIATE EDITOR
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    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.

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    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).

    SystemBenefitRiskLack of Effect
    Central nervous system
    Increased alertnessSleep disturbances
    Better attentionNervousness
    Increased concentrationJitteriness
    Increased focusIrritability
    Increased energyAnxiety
    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 strokeSlight blood pressure increases among regular drinkersNo 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 performanceNo effect in short-term sports activities
    Retardation of exhaustion feeling
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    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 ClassNameEffect on Caffeine Half-Life
    Oral contraceptivesAllAbout +40%
    Quinolone antibioticsAmi- and difloxacin+21%
    Ciproflacin+70%
    Enoxacin+75%
    FleroxacinNo effect
    Grepafloxacin+50%
    Lomeflaxin+23%
    Nalidixic acid+67%
    Norfloxacin+35%
    OfloxacinNo effect
    Pefloxacin+22–47%
    Pipemidic acid+59%
    RufloxacinNo effect
    TemafloxacinNo effect
    Tosufloxacin+34%
    TrovafloxacinNo effect
    Cardiovascular drugsMexiletine (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 drugsClozapine (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 drugsIdrocilamideHalf-life increased up to 63 h
    RofecoxibDecreased clearance
    Antifungal medicationFluconazole+ 25%
    IsavuconazoleNo effect
    Ketoconazole+ 11%
    Terbinafine+ 21%
    Proton pump inhibitorsCimetidine−31%
    LansoprazoleNo effect
    Omeprazole−41%
    PantoprazoleNo effect
    Ondansetron (anti-vomiting)Slows clearance
    Psoralens, anti-psoriasis and anti-eczema drugsMethoxsalen−70%
    5-Methoxypsoralen−31%
    BronchodilatorsFurafyllineIncreases caffeine half-life up to 10-fold
    TheophyllineSlows caffeine clearance, twofold
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    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).

    AnticonvulsantSpeciesType of Interaction
    Classic AEDs
    CarbamazepineRats, miceAcute and chronic caffeine dose-dependently decrease efficacy
    CarbamazepineHumansIncreases half-life by twofold; decreases bioavailability by 32%
    ClobazamHumansNo significant action on clobazam pharmacokinetics
    No interactions between clobazam and valproate or lamotrigine
    ClonazepamRatsNo significant effect
    DiazepamMiceDecrease in efficacy
    DiphenylhydantoinMiceDecrease in efficacy
    EthosuximideRatsDecrease in efficacy
    PhenobarbitalRatsNo significant effect
    MiceDecrease in efficacy
    PhenytoinMiceDecrease in efficacy
    ValproateRatsNo significant effect
    MiceDecrease in efficacy
    Second generation AEDs
    FelbamateMiceNo significant effect, decreased efficacy only at very high doses (100–160 mg/kg caffeine)
    GabapentinMiceDecrease in efficacy
    LamotrigineMiceNo significant interaction
    OxcarbazepineMiceNo significant interaction
    TiagabineMiceNo significant interaction
    TopiramateMiceDecrease in efficacy
    • View popup
    TABLE 4 

    Pharmacokinetic regulation of caffeine consumption linked to genetic polymorphism

    More details can be found in the text.

    EnzymeBiologic RoleClinical RelevanceReplicationLocation in Text
    CYP1A1CYP1A1 metabolizesAssociation with habitual caffeine consumptionYesIV.A.4
    – caffeine to paraxanthine, theobromine and 1,3,7-TMU
    – polycyclic aromatic hydrocarbons, which are important constituents of coffee
    CYP1A2Major enzyme involved in liver caffeine metabolismAssociation with habitual caffeine consumptionYesIV.A.1
    IV.A.4
    CYP2A6Metabolism of paraxanthine to 1,7-DMUNo clear link with consumption shown yetYesIV.A.1
    NAT2Metabolism of paraxanthine to AFMUNo clear link with consumption shown yetYesIV.A.2
    XOMetabolism of 1-MX to 1-MU1MU:1MX ratio used following caffeine administration as a pharmacodynamic measure of drug effect on XO activityYesIV.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.

    • View popup
    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.

    GeneBiologic RoleClinical RelevanceReplicationLocation in Text
    ADORA2AAnxietyModulation of anxiety levels in response to caffeine intakeYesIV.B.1.a
    AttentionInfluence on attentional processing and working memoryYesIV.B.1.a
    Emotional processingInfluence on startle reflexYesIV.B.1.a
    Maladaptive emotional processing
    Impact on the selection of relevant early information
    Panic disorderExtreme reactions to stressful situationsYesIV.B.1.a
    Agoraphobia
    SleepSusceptibility to hyperarousal-induced insomniaYesIV.B.1.b
    Sleep latency
    Modification of EEG sleep-linked characteristics
    Caffeine consumptionCarrying the 1976TT genotype decreases caffeine consumptionNoIV.B.1.c
    Adenosine deaminaseSleepRole in sleep architecture and maintenanceYesIV.B.1.b
    Controls the frequency of awakenings
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Pharmacological Reviews: 70 (2)
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1 Apr 2018
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Review ArticleReview Article

Variation in Caffeine Metabolism

Astrid Nehlig
Pharmacological Reviews April 1, 2018, 70 (2) 384-411; DOI: https://doi.org/10.1124/pr.117.014407

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Review ArticleReview Article

Variation in Caffeine Metabolism

Astrid Nehlig
Pharmacological Reviews April 1, 2018, 70 (2) 384-411; DOI: https://doi.org/10.1124/pr.117.014407
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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
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