What is First-Pass Metabolism?

Today’s article looks at first-pass metabolism, otherwise known as the ‘first-pass effect’. This phenomenon relates mainly to drugs and other supplements that are consumed orally. The concentration of a drug or supplement that we ingest is often not the amount that is eventually seen in the blood (systemic circulation). So, what gives? Where are we getting short-changed?  

It turns out the liver is the main organ responsible for this discrepancy, and to a lesser degree the gut.. First-pass metabolism (FPM) can either reduce (usually) or enhance (sometimes) the effect of drugs and supplements that we consume. FPM is an important facet of drug metabolism with implications for bioavailability and the eventual activity of the compound within the body. This article will explore how FPM works and will present several examples of FPM in action. 

How Does First-Pass Metabolism Work? 

Under normal circumstances in a hospital or other clinical setting, the concentration of a given drug or substance is measured in the peripheral circulation by obtaining a blood sample from one of your veins. When an amount of drug is lost between the site of administration (e.g., oral ingestion) and the site of measurement (e.g., peripheral venous blood), FPM is deemed to have taken place [1]. FPM is generally attributed to metabolism, predominantly in the liver but it also occurs in the gut, blood, lungs, and the cells that line blood vessels themselves (the epithelium).  

There are several routes that a substance or drug can take into the body, for instance via injection (into a vein or muscle), through the skin or a body cavity (e.g., suppository, transdermal, sublingual, buccal). All of these methods bypass the full extent of FPM, taking the liver out of the equation. As an example, the bioavailability of an injected drug (i.e., the fraction or percentage of an administered dose that reaches the systemic circulation) will be 100%. By contrast, oral ingestion or administration is susceptible to the influence of liver FPM.  

After a drug is orally ingested, it is absorbed through the gut and transported through the portal vein to the liver. There, the liver will metabolize the drug, using enzymes (mainly the cytochrome P450 family) in a complex series of reactions that culminate in water-soluble compounds that can be excreted in bile [2]. Unfortunately, a consequence of this process is that not much active compound may be left over to proceed to the systemic blood circulation. Therefore, orally ingesting a drug/supplement is likely to result in lower bioavailability than injecting it directly into the bloodstream under most circumstances. But there are exceptions to this (like methylene blue, see below!). 

The extent of FPM is affected by four physiological factors, of which the major ones are: enzyme activity, plasma protein and blood cell binding, and gastrointestinal motility [1]. Firstly, the specificity and content of enzymes (e.g., cytochrome P450 in the liver) and the variable expression of these (determined by genetic and environmental factors) largely underpins the variation in drug/supplement  bioavailability between individuals [3]. Drugs/supplements that undergo substantial FPM tend to show large individual variation in the concentrations that are eventually seen in the circulation – in other words the impact of FPM differs from person to person and must be considered when administering drugs/supplements in a clinical environment.  

Next, drugs/supplements can bind to plasma proteins (such as human serum albumin), which increases their solubility, reduces the risk of oxidation, lowers their toxicity, and reduces the impact of FPM. The level of protein binding depends on the properties of the drug but also the temperature and/or pH of the surrounding environment [4].   

Faster gastrointestinal motility, and therefore gastric emptying, tends to increase the amount of drug seen in the circulation as the liver is overwhelmed, whereas delayed/slower gastric emptying, as seen in the fed state, increases FPM due to the more manageable appearance of the drug from the small intestine. 

Elsewhere, FPM can occur in the lung (for example drugs relating to anesthesia [5]) as well as in the epithelial cells of the gut wall mucosa [6], causing reduced concentrations of drug in the systemic circulation. 

If a person exhibits a highly prominent FPM effect, administration by another route is usually necessary in order to bypass FPM and ensure the desired concentration can get where it needs to go. What’s more, certain drugs are not viable as oral agents, due to the significant extent of FPM [1], and therefore warrant administration by other means.  

What Factors Affect Bioavailability? 

There are several key variables that affect the bioavailability of a given substance within the context of FPM, and these comprise both source and subject factors [7]. 

Source factors include elements relating to the pharmaceutical formulation itself, such as the physical and chemical makeup of the substance, as well as the total ingested dose. For instance, the absorption of calcium added to wheat bran products can be impeded by the anti-absorptive effect of phytate contained within the bran [7]. Spreading the nutrient intake out over the course of a day can also enhance absorbability when compared with a single ingested bolus [8].  

Water-soluble compounds tend to be more bioavailable than non-water-soluble compounds, and therefore have more optimal drug delivery. One potential cause of this is acid degradation in the stomach. To get around this, liposomes are an emerging and popular method of encasing compounds with poor stability and/or solubility, enhancing their bioavailability [9]. 

Liposomes are spherical vesicles consisting of biodegradable natural or synthetic phospholipids (the same material as your cell membranes are made of). They encase the non-water soluble compound in a soluble lipid outer layer which enhances absorption and bioavailability. 

Subject factors are of little concern to pharmaceutical or supplement manufacturers because they lie completely outside their control [7]. These factors relate to things such as mucosal mass, intestinal transit time, and rate of gastric emptying that all vary at an individual level. Although uncontrollable from their perspective, it is nevertheless the role of the manufacturer to ensure that the constituents or properties of a formulation are optimized to ensure adequate bioavailability [7]. 

Below we will discuss selected substances and the impact of FPM on their metabolism and active effects.  

First-Pass Metabolism and Cannabinoids 

As we discussed at the beginning of this article, FPM plays a key role in the metabolism of many recreational and pharmaceutical drugs. Cannabis contains a variety of chemical compounds, including the well-known cannabinoids delta-9-tetrahydrocannabinol (THC) that possesses psychoactive properties, and cannabidiol (CBD) which is not psychoactive [10]. Both of these components are metabolized in the liver, yet the route of administration has varying effects on bioavailability and metabolism. 

Inhaling cannabinoids results in a similar pharmacokinetic profile to intravenous administration, with peak THC and CBD levels in the blood attained within 3 – 10 minutes [11]. The bioavailability of THC with this method ranges from 10 – 35% depending on factors that we alluded to above, such as the nature of inhalation, length of breath hold, the device used, and so forth [10].    

When consumed orally (‘edibles’), FPM comes into play and reduces the bioavailability of THC to less than 10% [12], suggesting an extensive impact. There is also a delayed effect, with peak concentrations in blood seen after two hours, a much slower uptake when compared with inhalation. This delay can potentially result in a greater amount of drug being consumed due the ‘lag’ in the onset of effect [13].  If you have ever taken more cannabis edibles because you didn’t “feel it” only to suffer later, this is why! 

Another important caveat of oral ingestion is that THC is absorbed from the gut and travels through the bloodstream to the portal vein and then the liver, where it undergoes FPM [13]. Liver enzymes (mainly cytochrome P450) convert a large portion of THC to its metabolite 11-hydroxy tetrahydrocannabinol (11-OH-THC), a potent psychoactive metabolite that is capable of crossing the blood-brain barrier. In this case, FPM can enhance the potency of orally ingested THC through the influence of metabolites (breakdown products) and by delaying or prolonging the active effect.    

Alcohol Consumption and First-Pass Metabolism 

Drinking alcohol results in lower blood ethanol concentrations compared with the intravenous administration of an equal volume of ethanol – this is FPM at work.  

In this setting, gastric ethanol is metabolized by alcohol dehydrogenase, the extent of which is influenced by the ethanol concentration of the beverage, age, gender, and the rate of gastric emptying, genetic factors, and other factors [14]. Interestingly, blood alcohol concentration is higher after consuming vodka/tonic on an empty stomach compared with beer or wine [15]. 

Gastric emptying appears to be a major modulator of ethanol FPM, in that a slower or delayed rate of emptying increases the time of exposure of gastric ethanol to alcohol dehydrogenase, and enhances FPM in the liver as well [14]. Lower blood alcohol in the fed state, as opposed to the fasted state, is due to the greater FPM seen in the fed state, thanks to slower gastric emptying and increased liver blood flow [16].   

The bulk of alcohol metabolism occurs in the liver due to the abundance of alcohol-metabolizing enzymes found there. Damage to the liver therefore reduces the body’s ability to eliminate alcohol [16].  

First-Pass Metabolism and Dietary Supplements (NAD+ and NAC)

Two notable dietary supplements with poor bioavailability are nicotinamide adenine dinucleotide (NAD+) and N-acetyl cysteine (NAC). In the first case, NAD+ (a crucial cellular energy molecule) is rapidly metabolized in the stomach, intestines, and liver before it can reach the systemic circulation and desired destination (muscle tissue). Likewise, NAC (an antioxidant supplement) was shown to have an oral bioavailability of 9.1% [17].  

These two supplements demonstrate the case for modified methods of delivery, such as liposomal preparations, as a workaround for this low bioavailability.  

Methylene Blue, Buccal Troches, and First Pass Metabolism  

Ah it’s our favorite compound, Methylene Blue! Methylene blue is quite unusual because it’s 100% bioavailable whether taken orally/swallowed, as a buccal troche, or IV. The difference, however, is the rate of absorption. If taken IV, methylene blue is 100% bioavailability instantaneously. If taken orally, swallowed or in a tincture, the effects of methylene blue may take 30 minutes or up to 2 hours after ingestion depending on gastric motility (fasted or fed state, respectively). 

Methylene Blue in buccal troche form dissolves into the bloodstream via cheek mucosa in 15 to 30 minutes, taking gastric motility issues out of the equation entirely. This leads to a very consistent onset of action whether in the fed or fasted state. In addition, buccal troches dissolve into the brain circulation directly, leading to rapid cognitive upgrades that would not be as pronounced with oral ingestion. 

So if you can’t go and mainline your methylene blue, the buccal troche is a rapid, efficient, pharmaceutical grade, and very likely very less expensive alternative! 


[1]        S.M. Pond, T.N. Tozer, First-Pass Elimination: Basic Concepts and Clinical Consequences, Clinical Pharmacokinetics. 9 (1984) 1–25.https://doi.org/10.2165/00003088-198409010-00001

[2]        R. Vaja, M. Rana, Drugs and the liver, Anaesthesia & Intensive Care Medicine. 21 (2020) 517–523.https://doi.org/10.1016/j.mpaic.2020.07.001

[3]        null Shen,  null Kunze,  null Thummel, Enzyme-catalyzed processes of first-pass hepatic and intestinal drug extraction, Adv Drug Deliv Rev. 27 (1997) 99–127.https://doi.org/10.1016/s0169-409x(97)00039-2

[4]        K. Wanat, Biological barriers, and the influence of protein binding on the passage of drugs across them, Mol Biol Rep. 47 (2020) 3221–3231.https://doi.org/10.1007/s11033-020-05361-2

[5]        D.L. Roerig, S.B. Ahlf, C.A. Dawson, J.H. Linehan, J.P. Kampine, First Pass Uptake in the Human Lung of Drugs Used during Anesthesia, Advances in Pharmacology. 31 (1994) 531–549.https://doi.org/10.1016/S1054-3589(08)60640-7

[6]        W.A. Colburn, A pharmacokinetic model to differentiate preabsorptive, gut epithelial, and hepatic first-pass metabolism, Journal of Pharmacokinetics and Biopharmaceutics. 7 (1979) 407–415.https://doi.org/10.1007/BF01062538

[7]        R.P. Heaney, Factors Influencing the Measurement of Bioavailability, Taking Calcium as a Model, The Journal of Nutrition. 131 (2001) 1344S-1348S.https://doi.org/10.1093/jn/131.4.1344S

[8]        R.P. Heaney, C.M. Weaver, M.L. Fitzsimmons, Influence of calcium load on absorption fraction, J Bone Miner Res. 5 (1990) 1135–1138.https://doi.org/10.1002/jbmr.5650051107

[9]        M. Daeihamed, S. Dadashzadeh, A. Haeri, M.F. Akhlaghi, Potential of Liposomes for Enhancement of Oral Drug Absorption, Curr Drug Deliv. 14 (2017) 289–303.https://doi.org/10.2174/1567201813666160115125756

[10]      C.J. Lucas, P. Galettis, J. Schneider, The pharmacokinetics and the pharmacodynamics of cannabinoids, Br J Clin Pharmacol. 84 (2018) 2477–2482.https://doi.org/10.1111/bcp.13710

[11]      F. Grotenhermen, Pharmacokinetics and pharmacodynamics of cannabinoids, Clin Pharmacokinet. 42 (2003) 327–360.https://doi.org/10.2165/00003088-200342040-00003

[12]      T.E. Gaston, D. Friedman, Pharmacology of cannabinoids in the treatment of epilepsy, Epilepsy Behav. 70 (2017) 313–318.https://doi.org/10.1016/j.yebeh.2016.11.016

[13]      D. Barrus, K. Capogrossi, S. Cates, C. Gourdet, N. Peiper, S. Novak, T. Lefever, J. Wiley, Tasty THC: Promises and Challenges of Cannabis Edibles, Methods Rep (RTI Press). (2016).https://doi.org/10.3768/rtipress.2016.op.0035.1611

[14]      C.M. Oneta, U.A. Simanowski, M. Martinez, A. Allali-Hassani, X. Parés, N. Homann, C. Conradt, R. Waldherr, W. Fiehn, C. Coutelle, H.K. Seitz, First pass metabolism of ethanol is strikingly influenced by the speed of gastric emptying, Gut. 43 (1998) 612–619.https://doi.org/10.1136/gut.43.5.612

[15]      M.C. Mitchell, E.L. Teigen, V.A. Ramchandani, Absorption and peak blood alcohol concentration after drinking beer, wine, or spirits, Alcohol Clin Exp Res. 38 (2014) 1200–1204.https://doi.org/10.1111/acer.12355

[16]      A.I. Cederbaum, Alcohol Metabolism, Clinics in Liver Disease. 16 (2012) 667–685.https://doi.org/10.1016/j.cld.2012.08.002

[17]      B. Olsson, M. Johansson, J. Gabrielsson, P. Bolme, Pharmacokinetics and bioavailability of reduced and oxidized N-acetylcysteine, Eur J Clin Pharmacol. 34 (1988) 77–82.https://doi.org/10.1007/BF01061422.