Supplement Metabolism Explained
Dietary supplements offer a myriad of health benefits, but it is important that what the research concerning a particular supplement is showing in vitro is what is actually occurring in humans in vivo. In order to make sure this occurs, it is important for the supplement to have high bioavailability, whereas many supplements are poorly bioavailable. The bioavailability of supplements depends on the molecular properties of the compound and the route of administration in the body. Bioavailability is the fraction of the drug or supplement that is given that will reach systemic circulation.
Methods of Administration
For drugs and supplements, there are several methods of administration. Oral administration (swallowing a pill, powder, etc) is the most used method for dietary supplements due to convenience, but also encounters the most issues when it comes to bioavailability. When a drug or supplement is consumed orally, it travels through the intestines, then to the portal vein, and then to the liver. Some metabolism occurs through enzymes in the intestines, but In the liver is where most metabolism occurs. After it is processed through the liver it will finally reach systemic circulation (becomes active). As said before, the amount of the drug or supplement that reaches systemic circulation is the amount of that compound which is really bioavailable.
First Pass EffectWhen the supplement or drug is processed through the liver before systemic circulation, this is known as the First Pass Effect. The first pass effect is where most problems are encountered with bioavailability due to Phase I and II metabolism in the liver, and can also be bypassed through different administration routes.
In order to bypass the First Pass Effect, a method of administration must be used that will prevent the drug or supplement from going through the liver before undergoing systemic circulation. There are several ways this can be done:
The first and most obvious way to bypass the First Pass Effect from the liver is delivering the drug or supplement via Injection. A compound can be injected Intravenously (IV), Intramuscularly (IM) or Subcutaneously (SubQ). Intravenous Injection is the most superior form of injection where the compound immediately reaches systemic circulation and 100% of the compound is absorbed. In fact, bioavailability of any compound is defined as 100% if it is delivered by IV injection1. Intramuscular injections may be used where the compound is less water soluble, but absorption of IM injections can be slow, depend on the water solubility of the compound, dispersion of the solution and blood flow at the injected site. Due to this, in some cases oral administration can have better bioavailability than IM injection2. Subcutaneous Injections are used when the compound needs to be delivered more slowly than an IV Injection.
Another way to bypass the First Pass Effect is by dissolving the supplement in your mouth sublingually (under the tongue) or buccally (against the cheek). This causes the supplement bypass the intestines and liver, and to travel into mucosal tissue, where it will then go into systemic circulation usually within 5-10 minutes 3. Using this method for compounds results in 3-10x greater absorption than taking the supplement orally. Not all compounds can be taken sublingually, for a supplement to pass through the mucosal membrane, it must be small enough to diffuse through, and must be fat soluble (lipophilic)4.
This way to bypass the First Pass Effect still involves taking the supplement orally. If the supplement is highly lipophilic, instead of going into the portal vein, these compounds can be absorbed in the intestinal lymphatic system. After being absorbed through the intestine, the lymphatic system then transports the compound into blood circulation, where it reaches systemic circulation. This method of delivery is very popular because of its ease of use, and relative ease to apply increased lipophilicity to many compounds. For this reason, creating liposomal supplements is an effective way to increase the lipid solubility of the compound, and will allow it to be absorbed through the lymphatic system. Again, doing this allows the supplement to bypass the liver, and can drastically increase bioavailability of previously poorly-bioavailable compounds5.
In some cases, a compound should not bypass First Pass metabolism, and therefore should be taken orally, such as in the case of prodrugs. When prodrugs are taken, they are in an inactive form, they are then converted into their active form when they are metabolized in the liver. Therefore, doing an IV Injection of a prodrug will result in zero active compound rather than 100%, because first pass metabolism is required to convert the compound into its active and usable form.
Before going systemic, drugs or supplements get metabolized. The metabolizing process is broken into 3 phases: Phase I, Phase II, and Phase III6.
Phase I Metabolism
Phase I Metabolism is where a class of oxidase enzymes, known as the Cytochrome P450 (CYP450) enzymes undergo reactions with the drug or supplement that add oxygen to the molecule in the form of a carboxyl (=O) or hydroxyl (-OH) group. (figure phase I). The purpose of these reactions from the CYP450 family is to make the drug more water soluble, so it can be excreted from the body through the kidneys. Drugs or supplements that are more water soluble are easier eliminated from the body.
Figure 2: Examples of CYP450 Reactions Occurring in Phase I Metabolism which increase the water solubility of the molecule.
The two most common enzymes of the CYP450 family are CYP3A4 and CYP2D6. With CYP3A4 being responsible for metabolizing over 50% of drugs, while CYP2D6 can vary in effectiveness per person, which results in some people who are able to metabolize drugs quicker or more slowly than others7.
Some substances are known to inhibit activity of CYP3A4, thus increasing the bioavailability of some compounds. One potent CYP3A4 inhibitor is 6,7-dihydroxybergamottin, which is the compound responsible for ‘the grapefruit effect.’ This compound is able to enhance the effects of many supplements, as well as anabolic steroids which are taken orally because they reduce the effect of liver metabolism action via the Phase I metabolism10.
Phase II Metabolism
In Phase II metabolism, enzymes called transferases; primarily UDP-glucuronosyltransferases (UGTs), transfer more polar molecules onto the drug in order to make it more water soluble. This process is also used to detoxify drugs which may otherwise be toxic, such as acetaminophen. These reactions are called conjugation reactions, and involve the transfer of an acetyl, sulfate, or glucuronate group to the drug or supplement8. An example of this Phase II metabolism on a supplement can be seen with curcumin, where curcumin undergoes the addition of a sulfate (sulfation) or glucuronate (glucuronidation) group.
This process converts curcumin to an inactive form, where it is then eliminated through the kidneys as waste. This process is the reason why curcumin has poor bioavailability.
Phase III Metabolism
Phase III metabolism involves further metabolizing of some compounds, though most do not need to undergo this process. Phase III is primarily responsible for moving metabolites and conjugates to excretion, where a gene family known as the transport system such as P-glycoprotein remove Phase II products from to the extracellular medium, where they are excreted from the body9.
To summarize, the effect of supplements completely relies on the bioavailability of that supplement. In order for a supplement to become active, it must reach systemic circulation. Experiments that take place outside of the body may not reflect the same effects that happen inside of the body due to bioavailability. A supplement that is taken intravenously will have 100% bioavailability. Consuming a supplement orally means it is metabolized in the liver, where It is subject to Phase I and Phase II Metabolism and converted to non-beneficial metabolites which are excreted from the body through the kidneys. Supplements with poor bioavailability (such as Quercetin and Curcumin) can still have their full effects in the intestines, since they are not yet metabolized in the liver. So, if using supplements for their benefits in the intestine, there is no need to be concerned about bioavailability. Taking a supplement sublingually or enhancing its fat-soluble properties, so it is absorbed through the lymphatic system are ways to bypass liver metabolism and drastically increase the bioavailability of a supplement which has poor bioavailability.
DISCLAIMER: These statements have not been evaluated by the Food and Drug Administration, these products are not intended to diagnose, treat, cure, or prevent any disease.