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P450 Enzymes and Drug Metabolism

By August 2, 2016Drug Metabolism

Cytochrome P450s (sometimes referred to as CYPs) are proteins involved in almost 75% of phase I drug metabolism. They are part of the heme cofactor superfamily and therefore hemoproteins. The active site of the P450 enzyme contains a heme-iron center. Most P450 enzymes will require a separate protein to deliver one of more electrons to reduce the heme-iron centre. They are predominantly involved in Phase I metabolism. The P450 enzymes are present in hundreds of isoforms in the human body. Different isoforms of P450 results in different reactions catalyzed and different molecules regulating that catalysis.

 

P450 Test

As P450’s are so important to drug metabolism, understanding genetic abnormalities in these enzymes can be a real help when it comes to pharmacotherapy. For instance, knowing a patient has a polymorphism of CYP2D6 that results in rapid metabolism of codeine will indicate that this patient will not see much pain relief from the drug.

 

The Rxight® genetic test covers a number of P450 enzymes. These are:

  • CYP2B6
  • CYP2C8
  • CYP2C9
  • CYP2C19
  • CYP2D6
  • CYP3A4/CYP3A5

Within these, CYP2C9, CYP2C19 and CYP2D6 are of significant importance, accounting for almost 35% of all phase I metabolism of clinically used drugs.

 

The P450 enzyme CYP2C9 is of significance in the breakdown of the commonly used anticoagulant warfarin. Polymorphisms in CYP2C9 account for a significant proportion of variation in dose requirements.

 

CYP2C19 is required for metabolism of 10% of medicines used today. It metabolizes a number of anti-ulcer drugs including the proton pump inhibitors (e.g., omeprazole, esomeprazole, lansoprazole, etc.). It has other clinically important polymorphisms regarding platelet drugs such as clopidogrel. These mutations can result in excessive anticoagulation and increase the risk of bleeds, or can result in little to no response from the drug.

 

CYP2D6 can result in the reactions discussed above relating to the opiate codeine, but it is also responsible for metabolizing a number of tricyclic antidepressants. Some polymorphisms can result in no response from the drug, or can result in drug reactions (e.g., serotonin syndrome).

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