|Cytochrome P450, family 2, subfamily D, polypeptide 6|
PDB rendering based on 2f9q.
|Symbols||; CPD6; CYP2D; CYP2D7AP; CYP2D7BP; CYP2D7P2; CYP2D8P2; CYP2DL1; CYPIID6; P450-DB1; P450C2D; P450DB1|
|RNA expression pattern|
CYP2D6, a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. In particular, CYP2D6 is responsible for the metabolism and elimination of approximately 25% of clinically used drugs. This enzyme also metabolizes several endogenous substances such as hydroxytryptamines and neurosteroids.
There is considerable variation in the efficiency and amount of CYP2D6 enzyme produced between individuals. Hence for drugs that are metabolized by CYP2D6 (that is, are CYP2D6 substrates), certain individuals will eliminate these drugs quickly (ultrarapid metabolizers) while others slowly (poor metabolizers). If a drug is metabolized too quickly, it may decrease the drug's efficacy while if the drug is metabolized too slowly, toxicity may result. Hence the dose of the drug may have to be adjusted to take into account of the speed at which it is metabolized by CYP2D6.
In addition, other drugs may function as inhibitors of CYP2D6 activity or inducers of CYP2D6 enzyme expression that will lead to decreased or increased CYP2D6 activity respectively. If such a drug is taken at the same time a second drug who is a CYP2D6 substrate, the first drug may affect the elimination rate of the second through what is known as a drug-drug interaction.
CYP2D6 shows the largest phenotypical variability among the CYPs, largely due to genetic polymorphism. The genotype accounts for normal, reduced, and non-existent CYP2D6 function in subjects. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice. 
The CYP2D6 function in any particular subject may be described as one of the following:
- poor metabolizer – little or no CYP2D6 function
- intermediate metabolizers – metabolize drugs at a rate somewhere between the poor and extensive metabolizers
- extensive metabolizer – normal CYP2D6 function
- ultrarapid metabolizer – multiple copies of the CYP2D6 gene are expressed, and therefore greater-than-normal CYP2D6 function
A patient's CYP2D6 phenotype is often clinically determined via the administration of debrisoquine (a selective CYP2D6 substrate) and subsequent plasma concentration assay of the debrisoquine metabolite (4-hydroxydebrisoquine).
The type of CYP2D6 function of an individual may influence the person's response to different doses of drugs that CYP2D6 metabolizes. The nature of the effect on the drug response depends not only on the type of CYP2D6 function, but also on the extent to which processing of the drug by CYP2D6 results in a chemical that has an effect that is similar, stronger, or weaker than the original drug, or no effect at all. For example, if CYP2D6 converts a drug that has a strong effect into a substance that has a weaker effect, then poor metabolizers (weak CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects; conversely, if CYP2D6 converts a different drug into a substance that has a greater effect than its parent chemical, then ultrarapid metabolizers (strong CYP2D6 function) will have an exaggerated response to the drug and stronger side-effects.
Genetic basis of variability
The genetic basis for extensive and poor metaboliser variability is the CYP2D6 allele, located on chromosome 22. Subjects possessing certain allelic variants will show normal, decreased, or no CYP2D6 function, depending on the allele. Pharmacogenomic tests are now available to identify patients with variations in the CYP2D6 allele and have been shown to have widespread use in clinical practice. 
|CYP2D6 allele and enzyme activity|
Ethnic factors in variability
Ethnicity is a factor in the occurrence of CYP2D6 variability. The prevalence of CYP2D6 poor metabolizers is approximately 6–10% in white populations, but is lower in most other ethnic groups such as Asians (2%). In African-Americans, the frequency of poor metabolizers is greater than for whites. The occurrence of CYP2D6 ultrarapid metabolizers appears to be greater among Middle Eastern and North African populations.
This variability is accounted for by the differences in the prevalence of various CYP2D6 alleles among the populations–approximately 10% of whites are intermediate metabolizers, due to decreased CYP2D6 function, because they appear to have the non-functional CYP2D6*4 allele, while approximately 50% of Asians possess the decreased functioning CYP2D6*10 allele.
Inhibitors of CYP2D6 can be classified by their potency, such as:
- Strong inhibitor being one that causes at least a 5-fold increase in the plasma AUC values, or more than 80% decrease in clearance.
- Moderate inhibitor being one that causes at least a 2-fold increase in the plasma AUC values, or 50-80% decrease in clearance.
- Weak inhibitor being one that causes at least a 1.25-fold but less than 2-fold increase in the plasma AUC values, or 20-50% decrease in clearance.
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