Interindividual Differences in Caffeine Metabolism and Factors Driving Caffeine Consumption

Abstract

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, -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.

Improving natural product research translation: From source to clinical trial

“…134,168,195,209 When known, relevant genetic variants exist, for example, in metabolism, specimens for genetic analyses should at least be collected and saved. • Age, sex, race/ethnicity, body size and composition, health status (especially with respect to outcomes of interest), co-medications, smoking, geography.…”

“…• Genetic and epigenetic data, including characterization of microbiota structure and gene expression, especially as they relate to ADME of the NP. 134,168,195,209 When known, relevant genetic variants exist, for example, in metabolism, specimens for genetic analyses should at least be collected and saved. • Sensory characteristics (texture, flavor, odor; pill, capsule, etc., number and characteristics) of products to be used in a NPCT must be acceptable to trial participants, who should not be able to distinguish amongst intervention(s) and controls.…”

CYP2B6 Genotype‐Dependent Inhibition of CYP1A2 and Induction of CYP2A6 by the Antiretroviral Drug Efavirenz in Healthy Volunteers

“…The main objectives of this study were to test whether (i) efavirenz alters the activity of CYP1A2 in healthy volunteers and (ii) the magnitude of the alteration correlated with genetic variation in CYP2B6 expression. Caffeine is extensively metabolized in humans with at least 17 metabolites identified in the urine following caffeine administration . Approximately 80–90% of the total caffeine elimination in humans is mediated via hepatic CYP1A2‐mediated demethylation to paraxanthine, and caffeine is a well‐established and validated probe drug for CYP1A2.…”

“…Caffeine is extensively metabolized in humans with at least 17 metabolites identified in the urine following caffeine administration . Approximately 80–90% of the total caffeine elimination in humans is mediated via hepatic CYP1A2‐mediated demethylation to paraxanthine, and caffeine is a well‐established and validated probe drug for CYP1A2. The secondary objective of this study is to explore the effect of efavirenz on the activities of CYP2A6, XO, and NAT2.…”

“…The secondary objective of this study is to explore the effect of efavirenz on the activities of CYP2A6, XO, and NAT2. CYP2A6, XO, and NAT2 are involved in the formation of caffeine metabolites . Although these enzymes catalyze minor metabolic pathways, which makes it difficult to validate against oral clearance of caffeine, urinary metabolic ratios of caffeine have been widely used as convenient markers of CYP1A2, CYP2A6, XO, and NAT2 activities in population, epidemiological, and DDI studies .…”