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Pharmacokinetics: Drug metabolism


Content Reviewers:

Yifan Xiao, MD

Pharmacokinetics refers to the movement and modification of medication inside the body. Or more simply, it’s what the body does to the medication and how it does it.

Alright, so once the medication get administered, it first has to be absorbed into the circulation, then distributed to various tissues throughout the body; metabolized or broken down; and finally, eliminated or excreted in the urine or feces.

You can remember this as ADME - Absorption, Distribution, Metabolism, and Excretion.

Okay, let’s focus on the metabolism. This is the process of converting a medication into a less, or more active form. These forms are also known as metabolites.

So in most cases, metabolic reactions turn an active medication into a less active, or inactive metabolite, which is then ready to get excreted.

Some medications though, are administered in an inactive form, also known as a prodrug, which needs to be metabolized into an active form within the body before they can produce the desired effect. But even those medications will eventually need to go through further metabolism in order to get inactivated and excreted.

Now, all these reactions are broken down into two main phases: phase I and phase II.

This classification is somewhat misleading though. For some medications Phase II may occur before Phase I, while others may undergo only Phase I or only Phase II.

In any case, both phases take place primarily in the liver, and to a much lesser degree, in the lungs, kidneys, and the walls of the small intestine.

So, let’s zoom into a liver cell, also known as a hepatocyte.

Phase I reactions are typically carried out by a class of enzymes called cytochrome P450, or CYP450 for short.

These enzymes hang out mainly in cell compartments, like the endoplasmic reticulum and the mitochondria.

They are often abbreviated as CYP followed by a number, which indicates the family; followed by a letter for the subfamily, and then a number again for the form, like CYP3A4 or CYP2D6.

What these enzymes do is convert non-polar, lipid-soluble medications into slightly more polar, water-soluble metabolites through oxidation, hydrolysis, or reduction.

Okay, let’s move on to Phase II reactions. These are conjugation reactions, meaning that the medications or metabolites are conjugated, or joined with another compound - like a methyl, acetyl, or sulfa group; glutathione; or glucuronic acid - so they include methylation, acetylation, sulfation, glutathionylation and glucuronidation.

These reactions create highly polar, water- soluble metabolites that cannot diffuse through cell membranes very easily, so they are trapped in the urine and eliminated by the kidneys.

Alright, there’s a huge variability in the rate of these metabolic reactions.

So first of all, this is due to the genetic variability between individuals. This means that, because of their genetic makeup, some people, known as poor metabolizers, have fewer enzymes, or enzymes that work more slowly and less effectively against certain medications.

So, these medications tend to build up in the body, resulting in dangerous side effects.

  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Clinical Studies on Drug–Drug Interactions Involving Metabolism and Transport: Methodology, Pitfalls, and Interpretation" Clinical Pharmacology & Therapeutics (2019)
  4. "Understanding drug–drug interaction and pharmacogenomic changes in pharmacokinetics for metabolized drugs" Journal of Pharmacokinetics and Pharmacodynamics (2019)
  5. "Pharmacokinetics in Drug Discovery" Journal of Pharmaceutical Sciences (2008)
  6. "Impact of Drug Transporter Studies on Drug Discovery and Development" Pharmacological Reviews (2003)
  7. "Multidrug resistance-associated proteins: Export pumps for conjugates with glutathione, glucuronate or sulfate" BioFactors (2003)
  8. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)