In our 3rd installment on pharmacokinetics, we will briefly discuss the "M" which is metabolism. This is not meant to be all inclusive but will hit some major points which are clinically relevant.

Metabolism occurs across many body systems and even within the bloodstream by various enzymes. The primary goal of metabolism is to make the drug more easily excreted either via the gastrointestinal tract or the kidneys. Some drugs are considered "prodrugs" in that their metabolism converts the inactive prodrug to the active drug. A common example of this is clopidogrel (Plavix), an antiplatelet agent used in the management of stroke, MI, or TIA. Most of these biotransformations take place in the liver, although they can also take place in a number of different tissues/organs through different enzymes, such as p-glycoproteins.

In the liver, metabolism tends to occur through Phase I (modifying drug) and Phase II (coupling of compound to drug such as glucuronide). Most of the clinician's concern has to do with Cytochrome P450 isoenzymes in the liver of which there are many but CYP 3A4 is the most common one involving drug metabolism but there are many! This of each CYP as a "door" in which the drug has to go through for metabolism.

When evaluating drug interactions, it is important to know 3 different terms. If a drug is simply metabolized by the isoenzyme, we call this drug a "substrate". The very commonly prescribed HMG CoA reductase inhibitors known as "statins" for cholesterol are common substrates of CYP 450 enzymes.

If the the drug slows metabolism through this enzyme, we call this an "inhibitor". The ritonavir component of Paxlovid (used for COVID-19 treatment) is a well known inhibitor of metabolism that would potentially result in other drugs having increased concentrations and toxicity when given with Paxlovid.

If the drug speeds metabolism through the enzyme, we call this an "inducer". Many anti-epileptic drugs such as phenytoin, carbamazepine, and phenobarbital are inducers. These drugs when given with substrates that are metabolized by the same enzyme would possibly decrease the concentrations of those drugs resulting in clinical failure.

An important skill is determining the clinical significance of these potential drug interactions. The clinician can use various resources such as Lexi-Comp, Micromedex, or even the official labeling of the individual drug(s) in questions. An important resource for COVID-19 drug interactions can be found through the University of Liverpool here: https://www.covid19-druginteractions.org/checker. Clinical experience and resources together along with a discussion with a pharmacist are great ways to ascertain the true significance of these interactions and whether alternative therapies are warranted.

Next edition we will focus on elimination/excretion as we conclude our series on pharmacokinetics. Check out our videos at teachmepharm.com on various pharmacotherapy agents as we apply these principles within individual drug therapies.

Have a great week.

Chris