Pharmacokinetics: Drug metabolism

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Introduction0:00–0:42

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.

Metabolism0:42–1:59

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.

Phase I Reactions1:59–2:50

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.

Phase II Reactions2:50–3:30

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.

Metabolizers3:30–4:28

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. On the flip side, there are ultra, or rapid metabolizers, whose enzymes metabolize and inactivate certain medications so fast that it’s difficult to achieve a high enough level of medication in the bloodstream.
On the other hand, a poor metabolizer taking a prodrug that needs to be metabolized into its active form will have a harder time seeing any effect, while ultra-rapid metabolizers will be more likely to experience side effects.

Enzymatic Activity4:28–5:03

Okay, but even the same individual may metabolize medications differently. At birth, metabolic enzyme systems are not fully developed, so newborns typically have difficulty metabolizing certain medications.
But as we age, enzymatic activity falls off again. So elderly individuals can’t metabolize medications quite as well.
Also, since most enzymatic reactions take place in the liver, a decrease in enzymatic activity may be due to chronic liver disease.
Now, there is also an enormous number of interactions between metabolic enzyme systems and the things they break down. So, let’s say an individual is given two medications at the same time that are metabolized by the exact same enzyme.

Interactions5:03–6:46

That enzyme will have trouble metabolizing both at the same time, so it’ll probably take longer to break them down! And the result will be that one, or both of these medications will build up in the bloodstream and have prolonged action.
In other cases, medications, foods, and even diet supplements might induce or inhibit metabolic enzyme systems, particularly the cytochrome P450.
This could be done by either increasing the synthesis of these enzymes or enhancing their activity so they metabolize more quickly.
Since these enzymes are involved in either activating or inactivating multiple medication, inducing or inhibiting one of them could potentially increase or decrease the activity of multiple medications.
In other words, there are tons of possible interactions and combinations for each enzyme and medication. As an example, let’s look at the anticoagulant warfarin, which is broken down by cytochrome p450.
An inhibitor of these enzymes like the antifungal fluconazole or even grapefruit juice, will cause warfarin to build up in the blood, which leads to severe bleeding.
An inducer like the antibiotic rifampin will cause increased metabolism of warfarin, so a larger dose will be needed to achieve the wanted effect.

Review6:46–7:27

All right, as a quick recap, metabolic reactions can transform either an active medication into an inactive metabolite, or an inactive medication, called a prodrug, into an active metabolite.
There are two phases - phase I is mediated by cytochrome P450 and involves oxidation, hydrolysis, or reduction; and phase II involves conjugation reactions.
Both of them take place in the liver, creating polar and water soluble metabolites, and are affected by genes, age, liver disease, and interactions with medications, foods, and supplements.