Our bodies immediately respond to any medication we take as an unwelcome intruder. The body’s attempt to oust foreign chemicals forms the basis of drug metabolism, and understanding this process is a critical component of drug development.

Tricky Terminology

During drug development, two analysis sets are completed: pharmacokinetics, better known as PK, and pharmacodynamics, often referred to as PD. Pharmacokinetics (PK) focuses on how the body affects a drug. In contrast, pharmacodynamics (PD) relates to how a drug affects the body.

Going Further With ADME

When we talk about a new drug’s pharmacokinetics, we’re diving into the world of ADME studies:

• Absorption: The process of a drug entering the blood circulation.
• Distribution: The dispersion of a drug throughout the body.
• Metabolism: The body’s recognition and breakdown of a drug into metabolites.
• Excretion: The elimination of the drug’s metabolites from the body.

The Metabolism Master

The liver is the real MVP when it comes to drug metabolism. It chemically alters drugs so they can be eliminated from the body. However, not all livers are genetically the same. Understanding the differences in how the liver handles prescription drugs is one more piece of the drug development/precision medicine puzzle.

Why It Matters

The liver houses many proteins, including a family of cytochrome P450 enzymes, that affect how we break down and remove small molecule drugs from the body. Knowing how drugs are metabolized by the liver helps determine safe, effective dosages for patients.

Drug Development Basics

Explore the commercial, regulatory, and scientific factors that pave the way for a successful launch in our 9-hour on-demand course, Drug Development Immersion. Learn enough to be dangerous! Start today by registering for our most popular course!

What’s In A Name

Cytochrome P450 enzymes are named using a systematic nomenclature based on their genetic origins. The naming convention begins with the letters “CYP,” which stands for cytochrome P450. It is followed by a number indicating the family of the enzyme and a letter/number combo denoting the subfamily. For example, CYP3A4 is a well-known cytochrome P450 enzyme.

The Genetic Factor

Patients can have variations in genes that code for proteins involved in drug metabolism. These genes alter a medication’s metabolism and effect on the body. For example, Plavix (clopidogrel) is a prodrug activated by the liver enzyme CYP2C19. It was designed to reduce blood clot formation. The drug was recalled when 14% of patients on Plavix suffered strokes or heart attacks due to blood clots. Investigation revealed that patients with a mutation in the liver enzyme CYP2C19 couldn’t activate Plavix, which made Plavix ineffective. This finding prompted the FDA to add a black box warning to the Plavix label stating that Plavix has reduced effectiveness in patients with a genetic variation in their CYP2C19 gene.

The Grapefruit Factor

Grapefruit juice lowers the activity of CYP3A4, an enzyme that metabolizes the following medications:

• Statins
• High blood pressure medications
• Anti-depressant/anti-anxiety medicines
• Erectile dysfunction medications
• Allergy medicines

Cocktail Fodder

A recent study analyzed the microbiome’s effect on medication response. Researchers found that the amount and species of microbiome influence drug PD, PK, and ADME and that prebiotics and probiotics may eventually be used to alter the gut microbiome, enhancing drug efficacy and reducing adverse drug events.