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Flashcards in Drug metabolism Deck (14):

What is biotransformation? What is the aim of it?

Where the body breaks down a drug through the action of enzymes.

Once inside us most drugs are transported to the liver, where enzymes start the process of breaking them down, known as biotransformation, before putting them to use. In other words, the liver is our recycling plant. In the case of good substrates, they are incorporated into the body's normal functioning. If they are bad, the liver enzymes work to detoxify and rid the body of these substances.

Biotransformation typically makes a drug more water soluble so it can be more easily excreted. (in the urine if metabolised by the kidney or in the bile if metabolized by the liver)


Why is biotransformation important?

- it is the major route of drug elimination
- it often activates or inactivates drugs
- it can produce toxic products
- it can be something that varies between different patients
- it explains many of the drug interactions


Biotransformation (metabolism) of drugs usually happens in one or both of two phases, describe these two phases.

Most of drug metabolism occurs in the liver.

Phase 1:
Phase 1 reactions act to introduce of expose functional groups on the drug that make it more polar. These phase one reactions can be grouped into three categories; oxidation, reduction and hydrolysis. Oxidation is the most common and this typically happens in the liver through the action of the cytochrome P450 system. This results in an intermediate reactive O2 species that is then more susceptible to phase two reactions.

Phase 2:
Phase 2 reactions involve the conjugation of the drug (adding a large molecule either directly or after phase 1) such as glucoronic acid, sulphate, acetyl and glycine. This results in a molecule that is polar, an ideal substrate for active transport and a good molecule for excretion.


What is the cytochrome P450 system? and where is this system found

The P450's are a superfamily of enzymes that catalyze the oxidation of drugs. They are found in many tissues of the body but primarily in the endoplasmic reticulum of the liver. Over 70% of drugs are metabolized by CYP's.


What is another name for cytochrome P450?

CYP, microsomal P450 and mixed function oxidase (MFO)


How does CYP in the gut wall impact on bioavailability?

It will cause metabolism of the drug at the gut wall before it enters the blood stream and therefore a reduction in the fraction of drug absorbed and so a reduction in availability.


Different CYP enzymes in the body act on different substrates eg medicines, fatty acids, steroids. Which ones act on medicines/drugs?

CYP 1,2 and 3


What CYP extensively metabolizes theophylline?
What relevance does smoking have for a patient that takes this medicine?


Any kind of smoke (can be produced by burning wood, vegetation, tobacco etc). This burning produces PAH's and these result in an increased production of CYP1A2 enzyme and therefore increased clearance of Theophylline. So people that smoke who are on Theophylline for asthma or something will need a higher dose than the equivalent non smoker. (increase dose 50-60%)


What CYP extensively metabolises ethanol? What interaction does this have with paracetemol?


Ethanol is not only metabolized by CYP2E1 but it also interacts with CYP2E1 as an inducer (enhances the action of CYP2E1).

CYP2E1 also has the action of converting paracetemol to NAPQI which is a dangerous metabolite. Therefore paracetemol shouldnt be taken with alcohol as the byproduct of paracetemol can cause liver cell damage.


What CYP extensively metabolizes warfarin? What is the importance of knowing there are polymorphisms in quite a lot of people that result in a lower than normal amount of this CYP activity?


In some people (espeshially caucasians - 25%) there is a polymorphism that results in a lower clearance of warfarin. This means that they are at higher risk of bleeding out as the anticoagulant drug stays in their system for much longer than normal.

This highlights the important of drug inidivdualisation!!


What CYP extensively metabolizes s-mephenytoin? (an acid pump inhibitor like omeprazole). what interaction does this have with clopidogrel.


In some people there is a polymorphism where there is low levels of the CYP2D6 and therefore there is lower clearance of the mephenytoin and so it works better as more drug remains in the system.

However those will normal CYP2D6 activity will have decreased effectiveness of the drug clopidogrel (an antiplatelet drug) as it give out-competed by omeprazole. Omeprazole blocks/occupies all of the CYP2D6 binding sites.


What is the marker drug for CYP2D6 and what other clinically relevant drugs does it metabolize? What interactions does it have?


Antidepressants (amitriptyline)), beta blockers (metoprolol), analgesics (tramadol, codeine)

There are several inhibitors to this enzyme and thus it explains why so many of these drugs metabolized by CYP2D6 have varying effects on different people.

For example, Fluoxitine is an inhibitor. If you start someone on the antidepressent amitriptyline and if fails to work then immediately switch to fluoxitine before letting the amitriptylline clear out of the body then it will inhibit the clearance of it as the CYP2D6 is preoccupied by the new drug.


What does CYP3A4 metabolise? What are some of its unfavourable drug interactions?

Simvastatin (a member of the statin family that reduces HDL cholesterol), protease inhibitor (used for anto HIV), and immunosuppressants.

Graprefruit juice is an inhibitor and St Johns Wort is an inducer of CYP3A4.


In conclusion, what are the two ways CYP activity can be altered by other drugs? And why is this important for prescribing drugs?

1. Induced
some drugs like ethanol or tobacco smoke induce the activity of some CYPs.

2. Inhibition
Many drugs competitively inhibit the action of CYP such as grapefruit which competitively inhibits CYP3A4 in the gut.

It shows how important it is to be aware of drug interactions and that drug dose needs to be individualised.