Cytochrome Enzymes and Glycoproteins: What You need to Know

Why are Cytochrome P450 and P-Glycoproteins so important?

Cytochrome (CYP) enzymes are responsible for the metabolism of over 70% of drugs in clinical use. They determine how much of the drugs that we absorb make it to the site of action. Glycoprotein (P-gp) transporters and CYP enzymes have significant overlap of substrates. Because of this they are often considered together.

CYP/P-gp interactions are prevalent throughout pharmacology and very significant to your clinical practice. Let me show you how.

Cytochrome P450

CYP are a group of enzymes that clear foreign substances, including drugs, from the body. Simply put CYP enzymes convert drugs from their active forms to forms that can be eliminated via urine or feces. They act mainly in the liver, metabolizing drugs primarily by oxidation processes.

P-Glycoproteins

P Glycoproteins (P-gp) are transporter proteins found in cell membranes. Simply put, PGPs pump foreign substances, including drugs, out of cells. This is known as transmembrane efflux hence P-gp transporters are commonly referred to as efflux pumps. They are located in the esophagus, stomach, and small and large intestines.

Mechanism of CYP/P-gp Drug Interactions

Many of the drugs currently in clinical practice interact with CYP enzymes and PGP transporters in some way. Those drugs are either substrates, inhibitors or inducers of the CYP/P-gp proteins.

Inhibitors decrease activity of these proteins

Inducers increase activity of these proteins

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Mechanisms of Inhibition and Induction

PGP and CYP enzymes are commonly considered together because their induction and inhibition have mirroring effects. Inhibition of both will decrease drug clearance, induction of both will increase drug clearance. PGP and CYP enzymes also share many inducers and inhibitors.

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Cytochrome P450 and P-Glycoproteins Explained

Clinically Significant CYP/P-gp Drugs

The degree to which CYP/P-gp drugs can induce or inhibit those proteins vary from weak to strong. CYP proteins also exist as different isozymes: 1A2, 2CP, 2C19, 2D6, 2E1 and 3A4.

Below is a list of clinically significant drugs that act as either inhibitors, inducers or substrates of CYP/P-gp proteins. CYP 3A4 has by far the most prevalent and significant interactions.

For a comprehensive list of CYP/P-gp inducers, inhibitors and substrates:

Michalets, E.L. (1998), Update: Clinically Significant Cytochrome P-450 Drug Interactions. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 18: 84-112. 

Below is an abbreviated list that is based on my experience. These are the ones you want to keep in the back of your mind. If you see any of these, it should trigger a need for close investigation for drug interactions.

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