Dr. Frank-Chris Schoebel
Dr. Frank-Chris Schoebel
Dr. Frank-Chris Schoebel has been working as a cardiologist in Düsseldorf for 25 years and was a member of staff at the Clinic for Cardiology, Pneumology and Angiology at the University Hospital Düsseldorf for more than 16 years, including 6 years as senior physician. To the profile.

Liver - important for side effects of drugs


The liver metabolizes drugs

For drugs to work optimally and not lead to side effects, the human body must be able to metabolize them. Sometimes it is only the biochemical processing by the body itself that "produces" the actually effective substance from a so-called pro-drug, a "pre-medication.

The liver is particularly important for the metabolism of drugs. It is the first major metabolic organ downstream of the intestine and thus the site of absorption of most drugs. In the liver, in turn, it is the cytochrome P450 system at the cellular level that is most important for the breakdown and conversion of drugs, above all other systems, because 90% of all drugs are processed here.

Cytochromes, also known as CYPs, are proteins that primarily convert water-insoluble substances into water-soluble substances. This enables them to be excreted more easily, for example via the kidneys. The organism requires different CYPs for different drugs. Humans, for example, have 57 different CYPs. One of the most important cytochromes is CYP3A4, which processes up to 50 percent of all drugs.

Metabolism of drugs: different for each person due to genetics

People are also genetically different with regard to the cytochrome system. If a single CYP, e.g. CYP3A4, varies in its expression, then we call this a gene polymorphism. These gene polymorphisms are a major reason why people react to drugs with different therapeutic effects and with undesirable side effects.

We distinguish:

  • slow metabolizer
  • normal metabolizer
  • fast metabolizer

"Slow metabolizer" means that a CYP works comparatively slowly due to a genetic modification. "Fast metabolizer" means that a CYP converts a given substance particularly quickly. This also explains why a substance can work well in some people ("normal metabolizer"), but not so well in others, for example because it is broken down too quickly ("fast metabolizer").

Genetically determined changes also explain some of the side effects of drugs. If the active medical ingredient is broken down too slowly ("slow metabolizer"), this can result in an excessive accumulation of the drug in the body. This in turn causes toxic side effects and the body is overwhelmed.

Drugs and food affect CYPs of the cytochrome P450 system

Drugs and foods can affect the function of CYPs. We distinguish:

  • Substrates
  • Inhibitors
  • Inducers

"Substrate" means that a drug is processed by a specific CYP, e.g. metoprolol via CYP 3A4. Thus, metabolism here depends essentially on how a single CYP is genetically determined.

It becomes problematic with "inhibitors". They more or less block a CYP and thus inhibit the degradation of other drugs. By the way, these can also be foods, such as grapefruit in the case of CYP3A4.

"Inducers", on the other hand, accelerate the metabolic rate of CYPs, e.g. St. John's wort in CYP3A4. Corresponding drugs are then broken down more quickly and are less effective in the people affected. Incidentally, this also applies to the combined use of the contraceptive pill with St. John's wort.

One drug often affects multiple cytochromes

Most people are prescribed several pills at once, for example in the treatment of coronary heart disease, heart failure or high blood pressure. This makes the breakdown of medications even more complicated.

Different drugs are degraded via the same metabolic pathway, e.g. metoprolol (beta-blocker), lercanidipine (calcium antagonist) and irbesartan (AT-blocker) via CYP3A4. Thus, even with a CYP3A4 "normal-metabolizer", an overload of CYP 3A4 can occur. Especially if the treated person is a "slow-metabolizer".

In most cases, the same drug uses different CYPs for degradation. The commonly used beta-blocker metoprolol, for example, is degraded via CYP3A4 and CYP2D. Other substances use far more and up to 7 CYPs. For commonly used cardiovascular drugs, one drug (substrate, inhibitor, inducer) interacts with an average of 2.1 CYPs.

Determining gene variants of the cytochrome system: a step in the right direction

Nowadays, genetic alterations of cytochromes can be determined easily and reliably by molecular genetic analysis in the laboratory using a blood sample. However, the costs for the necessary complete characterization range between 300 and 400 euros. These are only covered by some private health insurers and not at all by statutory health insurers.

At Cardiopraxis , we recommend such a test if there is a reasonable suspicion of a so-called gene polymorphism due to medication side effects. We advise you to do this above all if you expect to take medication for the rest of your life. In this way, current medications can be checked and side effects can be avoided later, even with new preparations.

Drug interactions: Here's how we take a practical approach at Cardiopraxis

The following sections are actually intended for physicians who want to learn how to deal with the cytochrome system in practice. If this is understandably too complicated for you, then feel free to skip to the last section "Side effect of drugs...".

Unfortunately, molecular genetic analyses are only occasionally available to us. So how do we go about this in practice at Cardiopraxis ? We keep a cytochrome list of almost all the drugs we use to treat your cardiovascular system. In this list we assign the different CYPs with their respective properties to the drugs. This list is just an example of how you can make the assignment.1

Step 1: Raise suspicion

Everything starts with a problem. For many drugs, we know the potential for interactions. For example, the cardiac rhythm medication amiodarone is a strong inhibitor of CYP2C9, and antihypertensives such as irbesartan and candesartan usually need to be dosed much lower.

If a person reports a new side effect, this may already indicate a degradation disorder caused by an altered CYP. This is especially true if it is a case of general intolerance.

Another starting point: If a new drug has a stronger effect on a substance that has been taken for a long time. Imagine, for example, that you have been taking the beta-blocker metoprolol at a low dose for years. Your heart rate at rest has always been around 72 bpm. Now you are additionally receiving the platelet blocker clopidogrel in the hospital. You now report new onset drowsiness and a heart rate of 56 bpm.

What happened?

Step 2: Clarify interaction between drug and cytochrome

In the first step, we look to see whether clopidogrel, which is suspected of having side effects, is processed via a CYP at all. If we do not have our CYP list at hand, then we look on the Internet in the "drugbank" database. Here we find the so-called pharmacokinetic property of the drug under "Predicted ADMET Features": "A" stands for "Adsorption", "D" for "Distribution", "M" for "Metabolism", "E" for "Excretion" and "T" for "Toxicity".

Column 1 "Property" lists the potential properties of the drug with respect to the CYP system. It was tested for this by laboratory chemistry, in this case the property as a CYP2D6 inhibitor.

Column 2 under "Value" indicates which property the drug actually has, e.g. inhibitor. In fact, clopidogrel is an inhibitor of CYP2D6.

Und in Spalte 3 finden Sie die Wahrscheinlichkeit dieser tatsächlichen Eigenschaft. Dabei werten wir 1,0 als hoch und <0,50 als niedrig. Im Fall von Clopidogrel besteht eine mittlere Wahrscheinlichkeit von 0,57, dass Clopidogrel ein Wirkung als „Inhibitor“ hat.


Step 3: Find intersection with other drugs

Now you have found out that your drug clopidogrel actually has an influence on the cytochrome system. You now need to see if other drugs intersect with clopidogrel at CYP2D6. You can do that again through "drugbank." If you have multiple drugs, it is sometimes easier if you read the entry for the cytochrome itself in the English Wikipedia, in this case "CYP2D6″. At the end of the Wikipedia entry you will find a fairly complete list of drugs that can interact with the cytochrome as substrates, inhibitors or inducers.

Step 4: Draw consequences

If we have a clinical suspicion of a gene polymorphism, we write that as a tentative diagnosis in our doctors' letters. We then try to avoid drugs in the future that are degraded via this metabolic pathway.

Side effects of medications - difficult analysis for the physician

You will have noticed by now at the latest that the evaluation of side effects is very complex, difficult and time-consuming, even for the prescribing physician. This means: The recommendation of medications is consequently also always associated with a high degree of responsibility.

You now also understand why it is almost impossible for a doctor to evaluate drug interactions once 5 medications have been taken.

All this also explains our principle in the Cardiopraxis: "As few drugs as necessary". This is not about following your individual wishes for few preparations, but simply a medical necessity.

In the future, we expect that the determination of drug-drug interactions will become more determinable and more predictable. The simple traffic light systems used to date, e.g. by pharmacies, are still too crude. The aim must be to record the individual genetically determined metabolic activity of cytochromes or their activity when several drugs are used. Artificial intelligence systems that can process large amounts of data will be helpful here. A molecular-genetic analysis of the cytochrome system in all people taking long-term medication would be optimal.


Links to individual drugs


Enter a drug at the top and scroll down until you reach the "Properties" section. There you will find the importance of the drugs in relation to different CYPs under "Predicted ADMET Features".

Links to individual cytochromes

Wikipedia links to the major CYPs for cardiovascular drugs.

1A2 2B6 2C8 2C9 2C19 2D6 2E1 2J2 3A4 3A5

Links marked in red indicate posts that contain lists of medications; you can find them there under "Ligands."


1TheCYP list is not guaranteed by Cardiopraxis . Intended for internal use at Cardiopraxis only.


 Cardiopraxis - Cardiologists in Düsseldorf & Meerbusch

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