THE PRIMER

When popping a pill, how often do we think about what happens next—to the pill or our bodies? Maybe we assume the body welcomes any extra help to soothe our headaches or control our blood pressure. This article looks into the mystery of what comes after the swallow.

Our bodies immediately respond to any pill (also known as a small molecule drug) we ingest as an unwelcome intruder. It tries to get rid of the alien lickety-split. The body’s attempt to oust foreign chemicals forms the basis of drug metabolism. Understanding this process is a critical part of drug development.

The liver functions as the most important organ when it comes to drug metabolism. So it makes sense to focus on the liver enzymes that metabolize small molecule drugs and how they work.

Have you ever noticed the warning label on certain prescriptions advising the patient to avoid grapefruit juice? It contains chemicals that can inhibit proteins essential to drug metabolism. Depending on the protein, the beverage either increases the amount of the drug in a patient’s bloodstream to potentially toxic levels or decreases how much medicine reaches its target in the body. Bad news either way.

The small intestine and the liver are home to one protein, CYP3A4. Grapefruit juice inhibits CYP3A4, which makes it accumulate in the patient’s bloodstream. These higher concentrations may cause direct toxicity or damage the liver over time. In general, higher than prescribed amounts of a drug force the liver to work harder. Only medicines broken down by CYP3A4 enzymes are potentially affected by grapefruit juice.

Other medications use transporter proteins on cellular surfaces that allow molecules to enter cells. Grapefruit juice inhibits these cellular gatekeepers, which results in lower drug concentrations. Reduced concentrations correspond directly with a decrease in how well a drug works. So if you enjoy an occasional glass of grapefruit juice, double-check your medication labels. Examples of medicines that mix poorly or even dangerously with the big citrus include:

• Statins, which help lower blood cholesterol levels, and include medications such as Zocor (Merck; Kenilworth, NJ) and Lipitor (Pfizer; New York City, NY), can result in increased levels via CYP3A4 inhibition.
• High blood pressure medications, such as Adalat (Bayer Pharma; Berlin, Germany), may cause toxicity.
• The anti-depressant/anti-anxiety medicines are Zoloft (Pfizer) or BuSpar (Bristol-Myers Squibb; New York City, NY). Drug levels may go up.
• Erectile dysfunction medications such as Viagra (Pfizer) and Cialis (Eli Lilly; Indianapolis, IN) may become toxic.
• Allergy medicines such as Benadryl (Johnson & Johnson; New Brunswick, NJ) and Allegra (Sanofi; Paris, France) may potentially lose some of their effectiveness.

Inhibiting CYP3A4 is not always a bad thing. Gilead Science’s (Foster City, CA) Tybost is a drug that inhibits cytochrome P4503A enzymes, another group of drug-metabolizing liver proteins. The inhibition increases the efficacy of certain antiviral drugs. Normally the enzymes break down these drugs. A combination of Tybost and the antivirals boosts the long-term concentrations of the antiviral medication, boosting their effectiveness. Tybost is approved both as a stand-alone drug and as a component of a four-drug-combination anti-retroviral therapy for HIV.

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The field of pharmacokinetics (PK) focuses on how the body affects a drug. In contrast, pharmacodynamics (PD) relates to how a drug affects the body.

Drug development includes studies, called ADME, to analyze a new product’s pharmacokinetics:

• Absorption: the process of a drug entering the blood circulation.
• Distribution: the dispersion of the drug throughout the body.
• Metabolization: the body’s recognition and subsequent breakdown of the parent compound into daughter metabolites.
• Excretion: the elimination of the drug from the body.

Some drugs are designed to be prodrugs—given to patients in an inactive or somewhat inactive form. The patient’s own metabolism then fully activates the drug. The anti-clotting medicine Plavix (Bristol-Myers Squibb) makes an excellent example of a prodrug.

When it first came to market, Plavix faced a recall. Nearly 14% of patients on the medication suffered strokes or heart attacks due to blood clots anyway. Further investigation revealed patients with a mutation in the liver enzyme CYP2C19 couldn’t activate the Plavix, making it ineffectual.

The continued sale of Plavix hinges on prospective patients taking a genetic test to see if they have the anti-Plavix mutation. Doctors prescribe patients with the mutation another medicine that acts by a different mechanism.

Two enzymes—CYP2D6 and CYP2C19—play a fundamental role in the metabolism of an estimated 25% of all prescription drugs. CYP2C19 has three variants, while the CYP2D6 gene has over 90 different variants. Depending on a patient’s combination of variants, he or she may metabolize the drug too quickly, too slowly, or in just the right way. Roche Diagnostics (Basel, Switzerland) markets a test that lets physicians rapidly determine a patient’s “metabolizer type” based on their specific combination of genes. The test, AmpliChip CYP450, uses SNP chip technology to assess a patient’s gene variants and ability to process certain prescription drugs safely.

Livers. They’re not all the same. Understanding the differences in how they handle prescription drugs is just one more piece of the precision medicine puzzle.

As we journey through the realm of pharmaceuticals, the enigmatic landscape of drug metabolism reveals itself as a pivotal player in the intricate process of healing. Our bodies’ intricate machinery engages in a dance of acceptance and resistance as foreign substances enter. The liver, the conductor of this symphony, orchestrates the metabolization of drugs with utmost precision. From the cautionary tale of grapefruit juice’s interference to the intriguing potential of enzyme inhibitors like Tybost, we uncover the delicate balance that dictates drug efficacy. The distinctions between pharmacokinetics and pharmacodynamics offer insights into the complex interplay between drugs and the body, while prodrugs like Plavix showcase the marvel of designing treatments that harness the body’s own mechanisms. Genotyping metabolism, with its nuanced genetic variants, propels us closer to personalized medicine, acknowledging that livers, like people, are far from uniform. The intricate world of drug metabolism stands as a testament to the remarkable intricacy of human biology.

1. What role does the liver play in drug metabolism?

The liver is a central player in drug metabolism, responsible for breaking down drugs into metabolites that can be easily eliminated from the body. This intricate process ensures that foreign substances are processed effectively to prevent toxicity or suboptimal drug responses.

2. How does grapefruit juice impact drug metabolism?

Grapefruit juice contains compounds inhibiting enzymes and transporter proteins involved in drug metabolism. This can lead to either increased drug concentrations in the bloodstream, potentially causing toxicity, or decreased drug levels, reducing the drug’s efficacy.

3. How does enzyme inhibition benefit drug development?

Enzyme inhibitors, like Tybost, can be beneficial in certain contexts. They can enhance the effectiveness of specific drugs by inhibiting enzymes that break down those drugs. This approach increases the drug’s concentration in the body and subsequently its therapeutic impact.

4. What is the difference between pharmacokinetics and pharmacodynamics?

Pharmacokinetics focuses on how the body affects a drug, including absorption, distribution, metabolism, and excretion. Conversely, pharmacodynamics studies how a drug affects the body’s physiological processes and molecular targets.

5. How does genotyping metabolism contribute to personalized medicine?

Genotyping metabolism involves analyzing genetic variants influencing how individuals metabolize drugs. This information helps doctors tailor treatment plans to a patient’s unique genetic makeup, optimizing drug efficacy and minimizing potential adverse effects.