Primer: Drug Metabolism

These posts, tagged “Primer,” are posted for two reasons: 1). to help me get better at teaching non-scientists about science-related topics; and 2). to help non-scientists learn more about things they otherwise would not. So, while I realize most people won’t read these, I’m going to write them anyway, partially for my own benefit, but mostly for yours.

I chose to work on this subject for December because I may end up teaching a lecture or two on metabolism in early February to pharmacy students.  Obviously I’ll go more in-depth with them, but that isn’t the purpose of these Primers: they are intended as introductions.

Merriam-Webster defines “metabolism” as such:

Metabolism –noun

a.  …the chemical changes in living cells by which energy is provided for vital processes and activities and new material is assimilated

b. the sum of the processes by which a particular substance is handled in the living body

This definition is all well and good, but we’re talking about a specific form of “metabolism” here, one that really is talking about the breakdown of a chemical compound not necessarily for the purpose of generating energy.

Wikipedia provides us with a separate definition for drug metabolism:

Drug metabolism is the biochemical modification of pharmaceutical substances by living organisms, usually through specialized enzymatic systems.

So when we’re talking about an individual, such as an athlete, that has a “strong metabolism,” we’re talking about related but separate processes from the ones typically involved in modification and removal of drugs from your system.

In general, drug metabolism consists of two separate processes known as Phases.  In Phase I metabolism, a given compound is broken down and typically inactivated (but not always, as we’ll see shortly).  It usually involves a specialized protein called an enzyme that removes a specific portion of the compound, rendering it pharmacologically inactive.  Phase II metabolism typically involves the addition of another molecule onto the drug in question, something we call a “conjugation reaction.”  This process serves to also increase the polarity of a given drug.  Usually, we think that Phase I reactions precede Phase II reactions, but not always.

When I say “polar,” I mean it in a sense similar to a planet, in that a planet has “poles” (e.g. north and south).  For the sake of simplification, you can also think of a magnet or a battery instead, with a “positive” pole and a “negative” pole.  In this fashion, chemicals also have a positive and negative charge, including chemicals like water:

In this case, the oxygen atom in water (i.e. H2O) is negative while the two hydrogen atoms are positive.  Therefore, water is polar: it has an end that is more positive and an end that is more negative.  Polar compounds are also considered “hydrophilic” (i.e. “water-loving”), mostly because these polar chemicals tend to dissolve readily in water.

There are examples of “hydrophobic” (i.e. water-fearing) chemicals as well, also known as non-polar.  You know how oil and water don’t mix?  That’s because oils like fats or lipids are hydrophobic and non-polar, made up of molecules that look kinda like these.

These are all examples of hydrophobic (non-polar) compounds, those that do not mix well with hydrophilic (polar) molecules like water.

The key to drug metabolism is to realize that most of your cells, and thus organs, are made up of lipids such as these, so if you have a drug that is particularly “lipophilic” (and thus, hydrophobic), then the drug is more likely to hang around in your body.  That is to say, a drug that is non-polar can hang around longer, affecting you for longer than you may otherwise want.  If you use a more polar drug (i.e. hydrophilic), it’s more likely to get passed out of your body much faster.  Much of your body’s ability to expel chemicals and metabolites depends on the ability of your kidney and liver to get those chemicals and metabolites into a form that works well with water, as water is what you typically get rid of (i.e. urine).

When your body recognizes a foreign compound, such as a drug, it wants to make that drug more polar so it can excrete it.  Thus, your liver contains a number of enzymes that do their best to make those foreign compounds more polar so you can get rid of it.

This process, obviously, impacts the ability of a drug to take action, which is why this process is important.  There’s a reason why drugs are introduced to your body orally (i.e. through the stomach/intestines), or intramuscularly, or intravenously.  If you were to take a drug orally, then it is subjected to what is termed as First-Pass Metabolism.  Typically, when you eat something, the nutrients from whatever you ate are taken up through the portal system and hit your liver before they hit your heart, which only then go on to the rest of your body.  Therefore, if you take Tylenol for a headache in a pill form, it some of it will be broken down in the liver before the heart gets it, and then it gets pumped to your brain to help with your headache.

Alternatively, you could take Tylenol intravenously, which bypasses the liver and thus gives you a full dose.  However, Tylenol is toxic in high doses, so you would never want to inject much of it (or any of it…there are better choices if that’s what you’re considering….) for fear that it could kill you.

The final concept to consider, aside from drug modification, polarity and first-pass metabolism, is how we could use this system to our advantage.  There are times when you take a drug, such as a benzodiazepine like valium (diazepam).  Valium, on its own, is very useful as a depressant, used to treat things from mania to seizures, however the act of drug metabolism produces metabolites that are also active (called, not surprisingly, active metabolites).  In the case of valium, it is broken down in the liver to nordiazepam, then temazepam and finally oxazepam.  Each one of these metabolites is active to some extent, which means that a single dose of valium will last for quite awhile as it’s broken down into other compounds that still affect you.

Sometimes, you can administer a non-active drug that then becomes active once it’s modified in your liver.  We call this a prodrug.  Codeine, for example, is modified by Phase I metabolism to its active form, morphine.  You typically administer morphine to someone intravenously, as it’s rapidly metabolized in the liver.  Codeine allows you to take advantage of your liver to give you morphine in a pill form, which you otherwise wouldn’t be able to do (as it would be broken down too far before it even hit your heart).

In short, drug metabolism is an extremely important process to consider when designing a drug.  You need to take ease of use and route of administration into account, you need to consider whether a drug has active metabolites or not, and you need to be aware of how hydrophilic/hydrophobic a drug is if you want it to remain in your body for any reasonable amount of time.

Leave a Reply

Your email address will not be published. Required fields are marked *