Caffeine Metabolism

Caffeine is a molecule consumed around the world for a variety of reasons, but let’s be honest, the main reason is to wake up – right? Well, while we may all be familiar with caffeine on a surface level and understand how it makes us feel, we likely have no idea how this wonderful molecule is processed in our body; well, in this article, we will examine just that – how is caffeine metabolized in our body?

What is Caffeine?

Caffeine is a molecule (C8H10N4O2) found in plants like the coffee bean, but can be (and is) synthesized outside of its natural environment for drug use [1][2].

Digestion & Absorption

Caffeine is readily absorbed by the small intestine, and depending on its delivery vehicle (food, liquid, etc.), it can also be absorbed in the mouth [3][4]. It is readily bioavailable with 99% absorption within 15-120 minutes, depending on method of ingestion [4][5][6]. Only 3% remains un-metabolized and is later excreted in urine [7].

Where is Caffeine metabolized?

Caffeine is primarily metabolized in hepatocytes found in the liver [6].

How is Caffeine Metabolized?

Caffeine, once it enters the cell, is metabolized by several different pathways, with the main pathway being the same as alcohol, and various drugs, known as the microsomal oxidizing system, found in the endoplasmic reticulum of the cell [8][9]. As with alcohol, caffeine is metabolized by the cytochrome P450 enzyme, but as this enzyme comes in many different isoforms, the enzyme isoform for caffeine is slightly different (CYP1A2) than the one acting on majority alcohol (CYP2E1) – both do act on one another, simply in minority [7][10][11]. Unfortunately, there is still much to be discovered about this particular isoform of P450, such as the substrates needed for particular metabolism and the other isoforms that act on caffeine, but we do know that this isoform is responsible for 90 - 95% of caffeine metabolism, so how it is metabolized [7][10]?

Hepatocytes (liver cells) make up the tissue of the liver, and within those cells, the endoplasmic reticulum metabolizes caffeine. 

Caffeine is metabolized via CYP1A2 isoform of cytochrome P450 [7][10][11]. This pathway uses a molecule of caffeine and demethylases, via CYP1A2 P450 (and a tiny bit from CYP2E1), to synthesize the primary intermediate paraxanthine (1,7 dimethylxanthine) [7][11]. Paraxanthine makes up 80% of the product coming straight off of the caffeine molecule, with 11% coming from theobromine, 4% in the form of theophylline, and 1, 3, 7-trimethyluric acid making up the final ~1% (these numbers are somewhat disputed, but the paraxanthine at 80% is accepted) [7][10]. These various products are possible, because the CYP1A2 enzyme seems to be able to attach to the caffeine molecule through various binding sites [10]. From here, paraxanthine is further demethylated to 7-methylxanthine via only CYP1A2, as well as 1,7 dimethyluric acid (via an unknown acting enzyme), 5-acetylamino-6-formylamino-3-methyluracil (via polymorphic N-acetyl-transferase enzyme), and possible other, unknown intermediates, and then through a variety of further mechanisms that demethylate and oxidize xanthine, the end product is a variety of methylated and unmethylated uric acids [6][7][12]. At this point, some small levels of caffeine that go unmetabolized, along with varying levels of every other metabolite mentioned here (and others) re-enter the blood stream, are carried to the renal system and excreted in urine [13].

[10]

This is highly dependent on circumstance. For example, in general, the half-life of caffeine is between 6-8 hours [14]. However, if a person is pregnant, their CYP1A2 activity decreases (likely due to the added load from pregnancy) and the half-life extends to 10+ hours [16][17][18]. Meanwhile, smokers see a 36% boost in CYP1A2 activity and therefor have a faster clearance of caffeine from their system (likely due to higher enzyme levels as P450 acts on many substances, even those associated with smoking) – this readjusts back down upon cessation [15][18]. So, there is variability based on situations impacting the effectiveness of the P450 CYP1A2 enzyme in the liver.

SUMMARY

So, there it is, caffeine is readily bioavailable with 99% digested and absorbed in 2 hours or less. Caffeine then travels to the liver, where liver cells act on the molecule with an enzyme that is responsible for many metabolic processes, depending on the variation of this enzyme. This enzyme begins the process of breaking caffeine down into a variety of intermediates before eventually being degraded to methylated and unmethylated uric acids, which are then shuttled out of the cell and excreted by the renal system. Caffeine’s half-life is between 6 and 8 hours, so it does take some time to be excreted if it goes through the metabolic pathways (3% is excreted, intact).

Writer: Nicolas Verhoeven
References

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[6] Institute of Medicine Staff. (2001). Caffeine for the Sustainment of Mental Task Performance: Formulations for Military Operations. Washington: National Academies Press.

[7] Thorn, C. F., Aklillu, E., McDonagh, E. M., Klein, T. E., & Altman, R. B. (2012). PharmGKB summary. Pharmacogenetics and Genomics, 1. doi:10.1097/fpc.0b013e3283505d5e

[8] Tymoczko, J. L. (n.d.). Lipid Synthesis: Storage Lipids, Phospholipids, and Cholesterol. In Biochemistry: A short course. Retrieved from https://books.google.com/books?id=WelFNV8akcwC&pg=PA448&lpg=PA448&dq=MEOS+caffeine+metabolism&source=bl&ots=GLHIWRRstV&sig=QetYA_AC75LlgUS4v1Cm8gpEz0M&hl=en&sa=X&ved=0ahUKEwjIgMCnlJ_RAhVD4iYKHdJjCJAQ6AEIPzAF#v=onepage&q=MEOS%20caffeine%20metabolism&f=false

[9] Lieber, C. S. (1969). Hepatic Microsomal Ethanol-oxidizing System. Journal of Biological Chemistry, 245(10), 2505-2512. Retrieved from http://www.jbc.org/content/245/10/2505.full.pdf

[10] Regal, K. A. (2005). OXIDATION OF CAFFEINE BY CYP1A2: ISOTOPE EFFECTS AND METABOLIC SWITCHING. Drug Metabolism and Disposition, 33(12), 1837-1844. Retrieved from http://dmd.aspetjournals.org/content/33/12/1837

[11] Gu, L., Gonzalez, F. J., Kalow, W., & Tang, B. K. (1992). Biotransformation of caffeine, paraxanthine, theobromine and theophylline by cDNA-expressed human CYP1A2 and CYP2E1. Pharmacogenetics, 2(2), 73-77. doi:10.1097/00008571-199204000-00004

[12] Lelo, A. (1989). Paraxanthine metabolism in humans: determination of metabolic partial clearances and effects of allopurinol and cimetidine. Journal of Pharmacology & Experimental Therapeutics, 248(1), 315-319. Retrieved from http://jpet.aspetjournals.org/content/248/1/315

[13] Rybak, M. E., Sternberg, M. R., Pao, C., Ahluwalia, N., & Pfeiffer, C. M. (2015). Urine Excretion of Caffeine and Select Caffeine Metabolites Is Common in the US Population and Associated with Caffeine Intake. Journal of Nutrition, 145(4), 766-774. doi:10.3945/jn.114.205476

[14] Gundert-Remy, U. (2015). Pharmacokinetic and Pharmacodynamic Effects of Caffeine. Retrieved from European Food Safety Authority website: https://www.efsa.europa.eu/sites/default/files/event/documentset/150305-p09.pdf

[15] FABER, M. (2004). Time response of cytochrome P450 1A2 activity on cessation of heavy smoking. Clinical Pharmacology & Therapeutics, 76(2), 178-184. doi:10.1016/j.clpt.2004.04.003

[16] KNUTTI, R., ROTHWEILER, H., & SCHLATTER, C. (1982). Effect of Pregnancy on the Pharmacokinetics of Caffeine. Obstetrical & Gynecological Survey, 37(8), 518. doi:10.1097/00006254-198208000-00004

[17] McKnight, K. K. (2013, April 1). Lifestyle changes for a healthy pregnancy: Caffeine, exercise, and more | Contemporary OB/GYN. Retrieved from http://contemporaryobgyn.modernmedicine.com/contemporary-obgyn/news/user-defined-tags/pregnancy/science-based-answers-prenatal-lifestyle-questio?page=full

[18] Thorne, C. F. (2011, June 6). Caffeine Pathway, Pharmacokinetics. Retrieved from https://www.pharmgkb.org/pathway/PA165884757

 

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