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What is First Pass Metabolism?

How does it affect drug efficacy?


A simplified liver cutout with pill capsules laying on it

First-pass metabolism, also known as the first-pass effect, is the degree to which a drug is metabolized or broken down at a specific location in the body, reducing the concentration of the active pharmaceutical ingredient (API) before it reaches the target site of action in the body or before it enters the systemic circulation.


For orally administered medications, the main location where first-pass metabolism occurs in the body is the liver. In addition to the liver, first-pass metabolism may also occur in other locations along the gastrointestinal tract as well as the lungs, the blood vessels, and other metabolically active tissues.


How are drugs broken down in the body?


The liver is where most drugs undergo chemical transformations that break down the drugs into metabolites, which are the byproducts of drug metabolism. These metabolites may be active, inactive, or toxic metabolites, which are then either used by the body (active metabolites) or eliminated more easily (toxic metabolites) after processing in the liver.


Active metabolites are the active components of a drug that are intended to achieve a specific therapeutic effect on the body, such as the reduction of symptoms. Inactive metabolites do not have any effect on the body—good or bad. Toxic metabolites are active compounds that can potentially cause harmful side effects in the body. The liver is involved in the process of detoxification and elimination of these harmful byproducts of drug metabolism.


So why does first-pass metabolism matter?


woman looking at medication

The problem with first-pass metabolism is that the degree of first-pass metabolism varies from person to person. First-pass metabolism may not impact some people or affect them only minimally, resulting in adequate bioavailability of the active pharmaceutical ingredient. This allows for a sufficient therapeutic dose of the active pharmaceutical ingredient to reach the target tissues, achieving the desired effect on the body.


On the other hand, first-pass metabolism can significantly affect other people, resulting in insufficient bioavailability of the active pharmaceutical ingredient and consequently worse drug effectiveness.


Why is first-pass metabolism different in each person?


Certain individual factors can influence the extent of first-pass metabolism, including:

  • Age of the person

  • Genetics

  • Biological sex

  • Enzymatic activity

  • Foods or other medications that might interact with the drug or how it is metabolized

  • Gastrointestinal (GI) motility

  • Plasma protein concentrations

  • How well organs such as the liver and kidneys function due to different disease states

a simple dna helix

Enzymes are proteins involved in the metabolism or breakdown of specific compounds or substances, including drugs. Certain foods, other medications, or alcohol can either induce or inhibit enzyme activity. Genetic variations can also play a role in enzyme expression and activity, resulting in differing degrees of drug metabolism.


Some people have slowed gut movement, known as peristalsis, or delayed emptying of the stomach (gastroparesis). Slowed GI motility may be due to the normal process of aging, hormonal influences, or even related to specific disease processes.


For example, slowed movement is a common symptom of Parkinson's disease (PD), and this slowed movement can also affect the stomach. Gastroparesis, or slowed or delayed emptying of the stomach contents into the intestines, frequently occurs in individuals with PD.


Slower transit times through the gastrointestinal tract keep the drug in specific locations for longer periods of time, leading to their increased breakdown, reduced concentrations of the active ingredient, and decreased drug efficacy.


For people with PD, slower GI motility has implications for the adequate absorption of PD medications like levodopa. Reduced absorption of levodopa due to the combination of gastroparesis and first-pass metabolism can lead to decreased control of PD motor symptoms and freezing of gait.


Plasma proteins are proteins in the blood that transport and distribute active drug ingredients to the target tissues, especially albumin, alpha-1 acid glycoproteins, and lipoproteins. If there are decreased amounts of these transporter plasma proteins that bind and carry the drug to the target site, the effectiveness of the available active ingredient decreases.


If specific disease processes lead to liver damage, the liver may not metabolize drugs very well, also affecting the extent of first-pass metabolism.


Are there solutions to first-pass metabolism to make sure drugs work well for everyone?


All of these individual differences can result in different levels of drug effectiveness when using a standard or fixed dose. The first-pass metabolism conundrum leads to problems with trying to determine effective dosing for each individual and may require the use of different routes of administration or manipulation of the drug's physical properties to help bypass the first-pass effect.


For example, some drugs may be administered sublingually (dissolving underneath the tongue) instead of orally (through the mouth and into the gut). This way, the active ingredient of the drug is absorbed directly into the bloodstream through the mucosal tissues in the mouth instead of having to undergo first-pass metabolism in the liver, which might reduce its bioavailability. Drugs can also be infused intravenously or injected into the muscle or under the skin.


Laxxon 3D printed medication pills

3D printing of pharmaceuticals also offers a solution to first-pass metabolism. 3D printing drug manufacturers can select polymers and other ingredients with specific properties to delay the release of the active pharmaceutical ingredient. They can also easily manipulate the drug parameters on the printer, changing the geometric shape of the printed tablet to specifically alter the timing of the active pharmaceutical ingredient's release.


This can make it easier to customize medication dosage to certain individuals, reduce unwanted side effects, and decrease treatment burden by eliminating the need to take more frequent doses of a drug throughout the day to achieve a specific therapeutic effect.


There are many ways in which the pharmaceutical industry is working to overcome the challenges posed by first-pass metabolism. 3D printing provides a personalized approach to pharmaceutical manufacturing, ensuring that people affected by first-pass metabolism receive adequate amounts of the active pharmaceutical ingredient in order to feel sustained symptom relief.

 
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Laxxon Medical is dedicated to engineering patented 3D pharmaceutical solutions that optimize products and benefit patients. Our goal is to establish SPID®-Technology as a manufacturing process with the individual and the pharmaceutical partner in mind.




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