Most individuals adjust their caffeine intake according to the objective and subjective effects induced by the methylxanthine. However, to reach the desired effects, the quantity of caffeine consumed varies largely among individuals. It has been known for decades that the metabolism, clearance, and pharmacokinetics of caffeine is affected by many factors such as age, sex and hormones, liver disease, obesity, smoking, and diet. Caffeine also interacts with many medications. All these factors will be reviewed in the present document and discussed in light of the most recent data concerning the genetic variability affecting caffeine levels and effects at the pharmacokinetic and pharmacodynamic levels that both critically drive the level of caffeine consumption. The pharmacokinetics of caffeine are highly variable among individuals due to a polymorphism at the level of the CYP1A2 isoform of cytochrome P450, which metabolizes 95% of the caffeine ingested. Moreover there is a polymorphism at the level of another critical enzyme, N-acetyltransferase 2. At the pharmacodynamic level, there are several polymorphisms at the main brain target of caffeine, the adenosine A2A receptor or ADORA2. Genetic studies, including genome-wide association studies, identified several loci critically involved in caffeine consumption and its consequences on sleep, anxiety, and potentially in neurodegenerative and psychiatric diseases. We start reaching a better picture on how a multiplicity of biologic mechanisms seems to drive the levels of caffeine consumption, although much more knowledge is still required to understand caffeine consumption and effects on body functions.

https://pharmrev.aspetjournals.org/content/pharmrev/70/2/384.full.pdf

Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption

Caffeine, theophylline, theobromine, and paraxanthine administered to animals and humans distribute in all body fluids and cross all biological membranes. They do not accumulate in organs or tissues and are extensively metabolized by the liver, with less than 2% of caffeine administered excreted unchanged in human urine. Dose-independent and dose-dependent pharmacokinetics of caffeine and other dimethylxanthines may be observed and explained by saturation of metabolic pathways and impaired elimination due to the immaturity of hepatic enzyme and liver diseases. While gender and menstrual cycle have little effect on their elimination, decreased clearance is seen in women using oral contraceptives and during pregnancy. Obesity, physical exercise, diseases, and particularly smoking and the interactions of drugs affect their elimination owing to either stimulation or inhibition of CYP1A2. Their metabolic pathways exhibit important quantitative and qualitative differences in animal species and man. Chronic ingestion or restriction of caffeine intake in man has a small effect on their disposition, but dietary constituents, including broccoli and herbal tea, as well as alcohol were shown to modify their plasma pharmacokinetics. Using molar ratios of metabolites in plasma and/or urine, phenotyping of various enzyme activities, such as cytochrome monooxygenases, N-acetylation, 8-hydroxylation, and xanthine oxidase, has become a valuable tool to identify polymorphisms and to understand individual variations and potential associations with health risks in epidemiological surveys.

Pharmacokinetics and Metabolism of Natural Methylxanthines in Animal and Man

Drug-metabolizing cytochrome P450 enzymes, the major phase I enzymes, are active in human liver already at very early stages of intrauterine development, although presumably at fairly low concentrations and in low numbers. During maturation, these enzymes go through various developmental programmes towards adulthood. The major increase both in abundance as well as in number of different enzymes takes place after birth, probably during the first year of life. Detailed information concerning these developmental changes is still limited. The major drug-metabolizing P450 enzymes appear to be primarily members of the CYP3A subfamily in all stages of development. The balance between different members of this subfamily, however, undergoes significant switches from the foetal predominant CYP3A7 to the major adult form CYP3A4. The ontogeny of the other cytochrome P450 enzymes is less well characterized, but the major switch-on appears to occur mainly after birth. Developmental expression of P450 enzymes is one of the key factors determining the pharmacokinetic status of developing individuals both pre- and postnatally.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0773.1998.tb01427.x

Developmental Expression of Cytochrome P450 Enzymes in Human Liver

The kinetics of caffeine elimination were followed in a ten month old female acutely intoxicated on a street form of the drug. Urine drug screening by gas chromatography-mass spectrometry also showed the presence of ephedrine, phenylpropanolamine, caffeine, theophylline and theobromine. Blood analyses using high pressure liquid chromatography gave evidence for the presence of theobromine, theophylline, caffeine and 1,7-dimethylxanthine. Sequentially taken blood samples determined that the initial stage of caffeine elimination was nonlinear. The Vmax =27.6 μg/ml/hr and Km = 284.6 μg/ml. At a plasma level of approximately 30 μg/ml the elimination became first order with ke = 0.097 hr-1 and t1/2 = 7.1 hr. The metabolic generation of theophylline and its elimination were also studied. Theophylline ke = 0.069 hr-1 and t1/2 = 10.0 hr. Elimination of both drugs was anomalously long for a child of this age.

John M. Metaxas

Papers

Toxicokinetics of caffeine elimination in an infant.