When popping a pill, we seldom think about what happens next—to the pill, or even to our bodies. We assume the body welcomes any extra help to fix the problem, but the reaction is quite contrary.

A swallowed pill (small molecule drug) is instantly labeled by our body as foreign and the reaction of our body is to immediately get rid of the unwelcome intruder. The process where the body breaks apart a drug in order to rid itself of the foreign chemicals is the basis of drug metabolism. Understanding this process is a critical part of drug development.

Since the liver is the primary site where medicine is metabolized, let’s focus on the liver enzymes responsible for metabolizing small molecule drugs and squeeze out some insight as to how these enzymes impact drug safety and efficacy.


Ever notice warning labels on certain prescription medications advising the patient to avoid grapefruit juice (GFJ)? Although considered a healthy food, GFJ contains certain chemicals that can inhibit key proteins involved in drug metabolism. Depending on which protein is inhibited, the result will either be an increase in the blood concentration of the drug (to potentially toxic levels) or a decrease in the amount of medication reaching target tissues.

Scenario 1: Increase in toxic levels of the drug.

CYP3A4, found in both the small intestine and the liver, is necessary for the metabolism of certain drugs. GFJ inhibits the activity of CYP3A4, resulting in a superabundant accumulation of the drug in the patient’s bloodstream. These higher concentrations may cause direct toxicity or liver damage over time. High drug amounts force the liver to work harder to metabolize the drug. Only medicines broken down by CYP3A4 enzymes are potentially affected by GFJ.

Scenario 2: Decrease in drug levels that reach the target tissues.

Some medications use transporter proteins—proteins on cellular surfaces that allow molecules to enter cells. GFJ inhibit these transporter proteins, which results in lower intercellular drug concentrations. Lower drug concentrations correspond directly with loss of drug effectiveness. Continue to enjoy what remains a healthy treat, but just be sure to double check your medication labels against the following examples:

  • Scientists have known for some time that statins such as Zocor (Merck) and Lipitor (Pfizer) can result in increased levels via CYP3A4 inhibition with GFJ.
  • More recent studies indicate GFJ consumption may create toxicity issues with medications prescribed to treat high blood pressure, such as Adalat (Bayer Pharma).
  • Drinking GFJ can cause escalated medication levels in Zoloft (Pfizer) and BuSpar (Bristol-Myers Squibb), both used as treatments for either depression or anxiety.
  • Erectile dysfunction patients should watch out when consuming GFJ because Viagra (Pfizer) and Cialis (Eli Lily) have potential to become toxic.
  • Allergy medicines such as Benadryl (Johnson & Johnson) and Allegra (Sanofi) potentially lose their effectiveness when consumed in tandem with GFJ.


Inhibition of CYP3A4 is not always a bad thing. Last week, the FDA allowed Gilead Pharmaceuticals’ (Foster City, CA) Tybost to fly solo, a drug whose primary function is to inhibit the cytochrome P4503A enzymes. Tybost was previously approved in 2012 as a component of a four-drug-combination anti-retroviral therapy used to treat HIV.

What is so special about Tybost? Some anti-viral drugs are normally broken down by cytochrome P4503A enzymes. When taken in conjunction with Tybost, the combination results in boosted concentrations of the antiviral medication for a longer period of time, resulting in greater efficacy.


Pharmacokinetics (PK) is how the body affects a drug and Pharmacodynamics(PD) is how a drug affects the body.

A necessary set of studies used during drug development to access Pharmacokinetics is called AMDE:

  • 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 removal of the drug from the body.


Some drugs are designed to be prodrugs—a drug given to patients in an inactive or less than fully active form—which is converted to the active form through metabolism. A good example of an accidentally discovered prodrug is the anti-clotting medication Plavix (Bristol-Myers Squibb, New York, NY).

Initially, Plavix faced a recall due to an elevated rate of ineffectiveness during treatment. As many as 14% of patients on the medication still experienced strokes or heart attacks due to blood clots. Further investigation revealed patients who had a mutation in the liver enzyme CYP2C19 were unable to activate the drug, thus rendering Plavix ineffective.

Plavix’s continued access to the marketplace hinges upon prospective patients taking a genetic test to determine whether they have the CYP2C19 mutation—the one that makes them unable to activate Plavix. Patients identified with the mutation are prescribed an alternative medicine that uses a different mechanism of action.

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