What Is First Pass Metabolism?

Reviewed by the BioHackers Lab Team | Last updated: February 2, 2023

When you take a drug, or supplement, your body normally won’t absorb all of it into your circulation. This mean what you see as the dose on on the supplement label is not what actually gets into your systemic circulation.

The Definition of First Pass Metabolism

According to Cambridge University Press, First Pass Metabolism is also know as first pass effect and is the degree of metabolic breakdown of a drug in the intestine or liver before it reaches systemic circulation.

First pass metabolism is also known as first pass effect or presystemic metabolism and according to Science Direct is defined as the presystemic metabolism or elimination, refers to the metabolism of drugs or chemicals in liver or intestine prior to their reaching the systemic circulation.

Here is a more detailed video that explains the process of how first metabolism works inside our bodies.

Key takeaway points are:

• A drug taken by mouth with be absorbed from the gastrointestinal (GI) tract into the liver
• The liver is a major metaboliser of drugs before allowing the active ingredients to enter our general (systemic) circulation
• This breaking down process of drugs by the liver is what is called First Pass Metabolism
• Some drugs have a heavy first pass effect, which means very little active ingredient will be allowed pass the liver into systemic circulation

Why Is First Pass Metabolism Important to Know?

1. Heavy First Pass Effect

What is a heavy first pass effect?

Heavy first pass effect is is when a substance undergoes significant metabolism and/or elimination of the active ingredient before entering systemic circulation where it can have an effect on target tissues in the body.

First pass metabolism can dramatically reduce the concentration of a drug or compound before it enters your circulation. This means that the amount you ingest of a drug is not always the amount that ends up in your bloodstream.

So, first pass metabolism affects the bioavailability percentage of a substance like drugs or supplements that reach systemic circulation and can be the reason for poor bioavailbility.

2. Prodrug Effect

What is a prodrug?

A prodrug can be defined as a drug substance that needs to be converted into the pharmacologically active agent by metabolic or physicochemical transformation.

An Overview of FDA Regulated Products, 2018

First pass metabolism is a factor that helps to convert an inactive substance into a pharmacologically active drug one in the body.

This means the liver can help make some example substances active in our bodies too and not just eliminate them.

Alternative Routes of Administrating Drugs

If a drug undergoes a heavy first pass effect when ingested orally then this is why you will see other recommended routes to administer certain types of drugs so that they are more effective.

These different ways to take some drugs to be more effective can include:

• Intravenous e.g. IV drips
• Rectal e.g. suppositories
• Subcutaneous injections
• Intramuscular injections
• Inhaled
• Transdermal
• Sublingual
• Buccal
• Aural
• Intra-arterial
• Intranasal
• Intravaginal
• Intra-articular injections

The First Pass Metabolism Effect on Some Example Substances

1. NAD and Its Precursors NMN and NR

Nicotinamide Adenine Dinucleotide (NAD+) supplements normally have a poor bioavailability when taken orally. This is because the nicotinamide adenine dinucleotide will undergo first pass metabolism and be broken down in the intestine before most of it enters the bloodstream.

This is why you will find NAD+ clinics and brands selling other routes of administration via an IV, transdermal or sublingual.

You will also find research looking into precursors of NAD like nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR) which are said to have better bioavailability when taken orally in supplement form by some researchers.

2. Methylene Blue

Methylene blue also known as Methylthioninium chloride is one of the oldest drugs that was first used to treat malaria back in 1891. It is also on the Word Health Organizations list of essential medications.

Methylene blue is also a major ingredient found in the nootropic Blue Cannatine by Trosctipions.

Methylene blue has a very good bioavailability when taken by mouth or intravenous at a rate of nearly 100%. So, it is not affected by first pass metabolism, but it can be absorbed quicker into the blood stream when taken as a buccal supplement vs oral tablet.

3. Nicotine

Nicotine is a naturally occurring substance found in trace amounts in the nightshade family and also in tobacco plants, but is manufactured to a pharmaceutical grade that can be used in other products.

According to Encyclopedia of Toxicology (Second Edition) nicotine has a large first pass effect. This would explain why in order to feel the effects of nicotine you would need to avoid oral ingesting and instead inhale nicotine or use it buccal or sublingually.

Nicotine has become a substance I know people use within the biohacking community to help act as a nootropic to help their cognition. It is also one of the active ingredients in Blue Cannatine.