Clinical significance of enzyme induction and inhibition

Published on October 1, 2007 Updated on July 27, 2016   33 min

Other Talks in the Series: Drug Metabolizing Enzymes

0:00
Ladies and gentlemen, my name is Kim Brosen. I'm a professor of clinical pharmacology at the University of Southern Denmark in Odense, Denmark. I'm going to talk to you about the clinical significance of enzyme induction and inhibition.
0:17
There is a Danish cartoon made by a Danish cartoonist called Robert Storm Petersen. It shows a physician who hands a prescription to a patient and says to the patient, "If this drug doesn't help, then come back, and I can prescribe you something else." And then the patient says: "Why don't I get something else right away?" And what we're going to talk about today is related to this everyday clinical situation that the outcome of a treatment is unpredictable because patients are different.
0:49
Patients are different both in their pharmacokinetics and pharmacodynamics because there are different host factors that influence the actions of drugs. Patients live in different environments. And patients are genetically different. And these three domains certainly also influence differences in drug metabolism.
1:11
Drug-drug interactions are something that can occur when two or more drugs are given concomitantly. And what it means is that one perpetrator drug changes the effect of another victim drug in a way which is not beneficial to the patient.
1:28
Usually, drugs are developed and made in such a way that the likelihood of giving interactions with other drugs is minimized. So therefore, it's quite common in clinical practice that drugs can be combined without any drug-drug interactions. Or there can be clinically unimportant drug interaction. It's rather unusual that there are clinically important drug interactions, which can be coped with by adjusting the dose or changing the dose regimen. And very rarely, drug-drug interaction is so dangerous that two drugs cannot be combined.
2:02
So the conclusion on drug interactions is that, given the number of possible interactions, the number of actual interactions is small. But it doesn't mean that the problem of drug interactions is negligible.
2:17
Like I said previously, drug interaction is a consequence of polypharmacy, which can be necessary if patients suffer from more than one illness. Sometimes it may be an advantage to treat the same illness with two or more drugs attacking different targets. Or the adverse effect of one drug can be dealt with by giving another drug. So there are many good reasons to combine drugs in clinical practice. But of course, we would like to avoid drug-drug interactions.
2:46
What this slide shows is the way in which the 200 most commonly used drugs in the United States of America are eliminated. 70% of all common prescription drugs are biotransformed in the liver. And of these 70%, that means 50% in total is oxidized by the cytochrome P450 enzyme system in the liver, which will form the focus of this presentation.
3:13
In humans, there are 57 CYP genes and 33 pseudogenes. They're organized into 18 families and 42 subfamilies. And the CYP enzymes that metabolize drugs by oxidation belong to the families 1, 2, and 3.
3:32
What this slide shows is the localization of the cytochrome P450 enzymes in the membrane of the smooth endoplasmic reticulum where the drug-metabolizing enzymes, together with a co-enzyme, which is a reductase NADPH. And oxygen is able to insert one atom of oxygen into the molecule of thousands of different drugs, which in this way, becomes more polar and, usually, less active.
4:03
There are two main types of drug-drug interactions in relation to drug metabolism. The one type is called the inhibition interactions, which may occur when two drugs that are both substrates of the same drug-metabolizing enzymes are given at the same time to patients. The two drugs may compete to binding to the active site. And this may impair the elimination of at least one of the drugs. Such interactions occur rapidly. They wear off rapidly. It's a direct chemical effect of one drug on the metabolism of another drug. And it's something which can be studied in vitro. The consequences are that drug concentration in blood may increase due to its impaired elimination.
4:50
The opposite, so to speak, type of interaction is called induction. And it's a biological phenomenon that starts gradually, wears off gradually, and usually is due to increased protein synthesis. And something which cannot be studied in vitro, but rather requires the experiments in animals or man.
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Clinical significance of enzyme induction and inhibition

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