Why the First Pass Effect is Important

Why the First Pass Effect is Important

Why the First Pass Effect is Important

by Dr Linda Klumpers

The first-pass effect (also called the first-pass metabolism) influences the body’s exposure to compounds. It makes the way compounds enter the bloodstream via oral route quite different from inhalation and transdermal administration. But, what is first-pass metabolism? Let’s find out in this blog post.

What is metabolism?

Metabolism is the body’s process of breaking down almost any material that enters it. The body metabolizes food, transforming it into useful energy and nutrients. The body metabolizes harmful foreign compounds from the outside environment, breaking them down into less harmful particles that can then exit the body. The body also metabolizes drugs, and most are metabolized into less active or inactive metabolites. Although metabolism happens throughout the body, most of it occurs in the liver.

The original compounds that enter the body are called parent compounds. After they are metabolized, they transform into metabolites.  

It is important to note that most drugs, cannabinoids included, are lipophilic (fat-loving). However, most of the liquids in our body consist of water. To be able to excrete these compounds via urine and feces, metabolism transforms most of them into their hydrophilic (water-loving) metabolites.

How does metabolism work?

After oral intake, a compound is digested in the gastrointestinal tract (GI tract), and then, from the intestine, absorbed into the bloodstream, via the portal vein, that carries it to the liver. There, the liver enzymes start specific chemical reactions when they come in contact with the compound, which facilitate its change from fat-loving to water-loving. Without this happening, compounds would stay in our fatty tissues for long periods of time.

The enzymes also play a significant role in the mechanism behind drug-drug interaction or drug-herb interaction, which we have discussed in this blog post.

The most important liver enzymes involved in cannabidiol (CBD) metabolism belong to the family of Cytochrome P450 (CYP).

The first-pass effect

When CBD and other cannabinoids are taken orally or transmucosally (e.g. via sublingual drops or buccal spray), the first-pass effect occurs. This phenomenon does not happen with any other administration route.

For example, when a drug is injected intravenously (IV), it is delivered into the central bloodstream in its entirety. With inhalation, a compound can get into the bloodstream directly from the lungs. From there, it travels to various organs, including the brain, before reaching the liver, where it is metabolized.

With the first-pass effect (see Figure 1), a compound travels from the GI tract to the liver, where it transforms into metabolites. After the metabolites and the remainder of the parent compound exit the liver, they will continue their way into the central bloodstream, which will distribute them throughout the body. Because of this phenomenon, the concentration of the parent compound and its metabolites in the blood after oral intake greatly differs from other routes.

Below is an example of what the parent compound and metabolite ratios can look like in the central blood circulation after different administration methods:


Therefore, the same dose of the same compound administered via different routes will have different effects on the body and brain.

After the first-pass metabolism

We just concluded that the same dose of a compound produces different effects due to the first-pass metabolism and the resulting difference in ratios of parent compounds to metabolites. Although that sounds understandable, let us take a look at why this happens and how you can use it to your advantage:

Less effect

Some compounds become less effective when they get broken down, which can be beneficial in some cases, but unwanted in others. Breaking down toxic compounds and thereby making them ineffective is an important way by which our bodies protect us from foreign toxic compounds. Various pesticides, for example, that stay on our plant-based food after harvest, would be harmful to us if it was not for our liver’s ability to break them down and protect us by detoxifying. (Schenkman, 1991) On the other hand, when we take medication, we often do not want our liver to break those down, as that would make the medication less effective. For this reason, the first-pass metabolism effect can be a struggle for many drug developers that want to develop their products for oral administration.

More effect

On the other hand, first-pass metabolism can also result in a metabolite that is as effective (possibly more effective) or more toxic than the parent compound. An example of the latter includes alcohol. Alcohol gets broken down in the liver by an enzyme called alcohol dehydrogenase. This conversion produces acetaldehyde, which is a toxic compound that is known to cause cancer and can be more toxic than the parent compound ethanol (alcohol). (NIAAA, 2007)

The main intoxicating compound of cannabis, THC, undergoes extensive first-pass metabolism after oral and oromucosal administration. One of the effects is that THC gets converted to 11-OH-THC during this process, which is known to be at least as effective as THC and is intoxicating by itself. (Lemberger, 1973) This metabolite is produced far less after other administration routes, such as with inhalation or transdermal products, which give different effects of varying strengths compared to oral and oromucosal routes.

What influences the first-pass metabolism?

Various factors influence if and to what extent the first-pass metabolism takes place. Firstly, the administration method determines whether a compound reaches the liver, and therefore gets metabolized there. Inside the liver, genetic factors can influence the activity of the metabolizing enzymes, and thereby the extent of the metabolism: some people will make fewer metabolites while others will make more than average. Additionally, environmental factors can play a role in the first-pass effect: how much compound is taken (the dose), and also the foods, medications, or supplements ingested can influence the activity of the enzymes, or their occupation (for an overview of drug-interaction, see this blog post).

The first-pass metabolism and CBD

CBD undergoes extensive first-pass metabolism when taken orally or transmucosally. The main metabolite of CBD is 7-COOH-CBD (Figure 2), but there are many more that humans produce, including 7-OH-CBD, 6⍺-OH-CBD, and 6ꞵ-OH-CBD. (Ujváry & Hanuš, 2016; Devinsky et al., 2018) Although it is likely, it is currently unknown whether CBD’s metabolites produce any effects, as is the case with THC’s metabolite 11-OH-THC. We also do not know what their pharmacological activity would be. It is also not discovered whether or to what extent CBD’s metabolites contribute to the known effects of CBD. CBD is mostly applied orally, sublingually, or buccally, and it is possible that CBD’s metabolites can influence the effects of CBD to some extent. It is up to future research to get more clarity on these and many other questions.


    • Metabolism is the body’s process of breaking down almost any materials that enter it.
    • The main role of metabolism is to break down compounds and nutrients to excrete them easier from the body.
    • After a compound travels from the GI tract to the liver, the first-pass effect occurs. It involves the transformation of the compound into metabolites, after which they get distributed throughout the body via the bloodstream.
    • Unlike THC’s metabolite 11-OH-THC which has an intoxicating effect on the body, it is still unknown whether CBD’s metabolites have any effects.


Figure 1:

After digestion in the stomach and intestine, a drug travels via the portal vein to the liver where the first-pass effect occurs. The liver enzymes break it down into metabolites, which then enter the central blood circulation and get distributed throughout the body.

Figure 2:

2A: CBD, the parent compound before metabolism

2B: 7-COOH-CBD, the most abundant CBD metabolite after intravenous and oral administration. (Ujváry & Hanuš, 2016; Devinsky et al., 2018)

We are now working with our friends at Cannify to bring you more information on important topics. Cannify researches and educates about cannabis. It is the first company to match patients and products with science. Cannify's founder Dr. Linda Klumpers earned a Ph.D. in Clinical Pharmacology of cannabis and has been studying cannabis for over a decade. Cannify educates an audience that includes patients, healthcare providers, and university students, and is actively involved in various cannabis-related research projects.


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