The first pass effect (FPE), also called first-pass metabolism (FPM) or presystemic metabolism, is a process where drugs are broken down in the body before they reach the place where they work or enter the bloodstream. This process is most common with medicines taken by mouth, but some drugs can still be broken down this way even if they are given through other methods, such as through a vein (IV) or into a muscle (IM). During this process, some of the drug is lost as it is absorbed, usually in the liver and the lining of the stomach and intestines. The liver is the main place where this happens, but it can also occur in the lungs, blood vessels, or other parts of the body that process drugs.

Drugs that are significantly affected by the first pass effect include buprenorphine, chlorpromazine, cimetidine, diazepam, ethanol (drinking alcohol), imipramine, insulin, lidocaine, midazolam, morphine, pethidine, propranolol, and tetrahydrocannabinol (THC).

First-pass metabolism should not be confused with phase I metabolism, which is a different process.

Factors

First-pass metabolism can happen in the liver for certain drugs, such as propranolol, lidocaine, clomethiazole, and nitroglycerin, or in the gut for drugs like benzylpenicillin and insulin. The four main systems that influence the first-pass effect of a drug are enzymes in the stomach and intestines, enzymes in the walls of the stomach and intestines, enzymes from bacteria, and enzymes in the liver.

Hepatic first-pass

After a water-soluble drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It travels through the portal vein to the liver before moving to the rest of the body. The liver breaks down many drugs, often to the point that only a small amount of the active drug leaves the liver and enters the rest of the circulatory system. This first pass through the liver can greatly reduce how much of the drug is actually used by the body.

An example of a drug affected by first-pass metabolism is the antiviral drug remdesivir. Remdesivir cannot be taken by mouth because most of the drug would be trapped in the liver, with very little reaching the rest of the body or the cells it needs to treat, such as cells infected with SARS-CoV-2. Because of this, remdesivir is given through an IV infusion, which skips the portal vein. However, some drug breakdown still happens in the liver due to second pass metabolism, where some blood from the liver returns to the hepatic portal vein and passes through liver cells.

Drug design

In drug design, drug candidates may have good drug-like properties but may not work well due to first-pass metabolism, which is specific to certain chemical reactions. Physiologically based pharmacokinetic models (PBPK) are used to predict first-pass metabolism. However, these models need adjustments for each drug because factors like how well the drug moves through the intestines vary. Enzyme levels also differ between people, which can affect how efficiently the drug is processed and how much of it reaches the bloodstream.

Cytochromes P450, especially CYP3A4, are important in first-pass metabolism. They influence how much of the drug enters the bloodstream.

Mitigation

Changing a drug into a prodrug can help avoid first-pass metabolism, which can improve how much of the drug reaches the bloodstream. In laboratory models, such as microfluidic chips that mimic the gut and liver, researchers can study first-pass metabolism more accurately, helping to create drugs that are absorbed more effectively.

Other ways to take drugs, like inhaling, using a rectal method, injecting, applying to the skin, or placing under the tongue, can avoid or reduce the first-pass effect. These methods let drugs enter the bloodstream directly.

Drugs that undergo a lot of first-pass metabolism usually need a much larger dose when taken by mouth compared to when taken under the tongue or through injection. People may need different amounts of the drug when taken by mouth because of differences in how much first-pass metabolism occurs, along with other factors. For some drugs, taking them by mouth may work better in people with liver problems. Bioavailability can also increase if another drug is taken at the same time that uses the same enzymes in first-pass metabolism, like propranolol and chlorpromazine.