What Is a Prodrug? How Prodrugs Work, Examples, and More

The concept of a prodrug was first described in the late 1950s, but prodrugs have existed for more than a century. First marketed in 1899, aspirin is one of the first prodrugs that was widely used. It turns into a substance called salicylic acid after it enters the body.

Over the years, researchers have made different prodrugs to enhance medications. They can help improve a medication’s effectiveness or avoid certain side effects.

Read on to find out how prodrugs are different from other medications and how using them can be helpful in certain situations.

What are prodrugs?

The International Union of Pure and Applied Chemistry defines a prodrug as a chemical that is transformed before it has pharmacological effects. In other words, after you take a prodrug, it changes in your body before it starts working.

There are two major types of prodrugs. These categories are based on how prodrugs are  converted in the body:

1) Type I prodrugs turn into their active forms inside of cells.

2) Type II prodrugs turn into their active forms outside of cells, such as in blood or other fluids.

Before a prodrug can provide its intended effects in your body, it needs to be broken down. A prodrug’s type affects how the medication is transformed or activated — whether it occurs inside or outside your cells. 

Different types of prodrugs can also impact drug interactions. Certain interactions may prevent a prodrug from becoming active.

Let’s look at an example. Clopidogrel (Plavix) is a medication that can prevent heart attacks and strokes. It’s a prodrug that's absorbed in the intestine and activated in the liver. Acid-reducing medications like omeprazole (Prilosec) can make clopidogrel less effective by preventing it from becoming active.

How are they different from other medications?

Prodrugs are different from other medications. They’re converted into their active forms after you take them. Certain enzymes (proteins) and chemicals make this conversion possible.

Prodrugs are inactive, or they’re significantly less active than their active forms. In comparison, other medications are already active and ready to work after you take them. They don’t need to be converted into different chemicals before being able to work.

How do they work?

Prodrugs contain nontoxic chemicals that change or hide certain features that the active medications have. When prodrugs enter the body, chemical reactions or enzymes activate them. These common enzymes are cytochrome P450 enzymes. They’re found in the liver and digestive tract.

Prodrugs are designed in two different ways. This includes:

1) Carrier-linked prodrugs: This is a prodrug that’s connected to an active medication. This connection breaks when it enters the body.

2) Bioprecursor prodrugs: These are chemically-modified versions of a medication. Different enzymes transform them into active medications.

Why are prodrugs used?

There are two general benefits of prodrugs. One main benefit is improving a medication’s effectiveness. Another benefit is reducing a medication’s toxicity or side effects.

One key way to improve effectiveness is by improving absorption. Absorption helps make sure that a medication reaches high enough levels in the body or gets into cells to achieve its intended purpose. Prodrugs help with this goal.

Other common reasons for making and using prodrugs include:

• Helping medications travel to their site of action (where they need to work)

• Impacting how medications are distributed to specific locations in the body

What are examples of prodrugs?

About 10% of all medications in the world are prodrugs. Their design seems to be gaining in popularity with time. For example, between 2008 and 2017, about 12% of all new FDA-approved medications were prodrugs.

Below are eight examples of prodrug medications that are used to treat different health conditions.

1) Clopidogrel (Plavix)

Clopidogrel (Plavix) is a blood thinner used to prevent heart attacks and strokes. It’s also a prodrug. After you swallow clopidogrel, it’s converted into its active chemical form. Different enzymes in your liver, such as CYP2C19, help make this happen.

But the FDA has added a boxed warning, indicating that some people may break down clopidogrel more slowly. This is due to slower CYP2C19 enzymes responsible for breaking it down. Clopidogrel may be less effective for these people. Genetic testing is available to identify genetic differences in CYP2C19.

2) Enalapril (Vasotec, Epaned)

Enalapril (Vasotec, Epaned) is a prodrug used to treat high blood pressure and heart failure. It’s converted to its active form, enalaprilat, which works as an angiotensin-converting enzyme (ACE) inhibitor.

3) Prednisone

Prednisone is a corticosteroid prodrug used for different conditions. This includes asthma, allergies, and arthritis. Prednisone turns into its active form, prednisolone, and it provides anti-inflammatory and immune system effects.

4) Azathioprine (Imuran)

Azathioprine (Imuran) is a prodrug for mercaptopurine. It’s used to alter the immune system in people who have rheumatoid arthritis or have an organ transplant. It’s also used off-label for purposes such as Crohn’s disease.

One of the main enzymes that converts azathioprine to its active chemical form is thiopurine S-methyltransferase (TPMT). You may be more likely to have side effects if you have different versions of the TPMT enzyme in your body. Your healthcare provider may recommend testing for your specific TPMT gene or enzyme activity.

5) Valacyclovir (Valtrex)

Valacyclovir (Valtrex) is a prodrug of acyclovir (Zovirax). Acyclovir can treat and prevent different infections that viruses cause. This includes genital herpes, cold sores (herpes labialis), and shingles (herpes zoster). It's sometimes used off-label to treat and prevent chickenpox (varicella zoster). Valacyclovir doesn’t get broken down as easily as acyclovir, so it doesn’t need to be dosed as frequently. 

6) Valganciclovir (Valcyte)

Valganciclovir (Valcyte) is a prodrug of ganciclovir. This is a medication used to treat and prevent cytomegalovirus (CMV). CMV infections can be especially harmful for people with weaker immune systems. When taken by mouth, valganciclovir helps improve how much ganciclovir your body absorbs.

7) Irinotecan (Camptosar)

Irinotecan (Camptosar) is a prodrug of the active medication SN-38. SN-38 is a strong substance that’s used as chemotherapy for different types of cancer. On its own, SN-38 isn’t absorbed very well by your body.

8) Codeine

Codeine is a strong pain reliever. It's a type of opioid used to treat pain. After entering the body, an enzyme called CYP2D6 transforms codeine into morphine. There are many differences in CYP2D6, so some people may be more sensitive to codeine than others. This is why the American Academy of Pediatrics recommends against using codeine in children.

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Written by:

Kevin Le, PharmD, BCPS, BCPPS

Kevin Le, PharmD, BCPS, BCPPS is a clinical pharmacy specialist in solid organ transplant at Ann & Robert H. Lurie Children’s Hospital of Chicago. He has been working as a pediatric pharmacist since 2016.

Edited by:

Joshua Murdock, PharmD, BCBBS

Joshua Murdock, PharmD, BCBBS, is a licensed pharmacist in Arizona, Colorado, and Rhode Island. He has worked in the pharmacy industry for more than 10 years and currently serves as a pharmacy editor for GoodRx.

Reviewed by:

Alyssa Billingsley, PharmD

Alyssa Billingsley, PharmD, is the director of pharmacy content for GoodRx. She has over a decade of experience as a pharmacist and has worked in clinical, academic, and administrative roles.

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