The CYP2D6 gene is localized on chromosome 22q13.1. Though the CYP2D6 enzyme represents only a 2 -4% of all hepatic P450s, its role in drug metabolism is extensive. It is one of the most investigated CYPs in relation to genetic polymorphism in the field of pharmacogenetic testing.1


Till now, more than 80 allelic variants of CYP2D6 have been reported. Among those, the most important variant are CYP2D6*2, CYP2D6*3, CYP2D6*4, CYP2D6*5, CYP2D6*10, CYP2D6*17 and CYP2D6*41. The most common CYP2D6 allele in the world as well as in Asians is CYP2D6*10 with an allele frequency of >50%. The encoded enzyme has a deleterious P34S mutation resulting in a very unstable enzyme along with reduced affinity for the substrates. Among Blacks, CYP2D6*17 is the major variant CYP2D6 allele which encodes, two missense mutations, as also seen in CYP2D6*2, and also T107I, which apparently makes an altered active site structure. This creates an altered substrate specificity. Overall, the enzymatic activity of the CYP2D6.17 is lower than the wild-type CYP2D6 enzyme. CYP2D6*41 is a variant of CYP2D6*2 having _1584 C instead of G. Subjects homozygous for this allele are phenotypically like individuals of the intermediary phenotype (IM) with one deficient CYP2D6 allele. 1


CYP2D6 is of great importance for the metabolism of clinically used drugs as about 20–25% of drugs are metabolized by it. Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, antipsychotics, antiarrhythmics, antiemetics, beta-blockers and opioids.2


There is a large inter-individual variation in the enzyme activity of CYP2D6. Ranging from ultra-rapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). The polymorphism of CYP2D6 significantly affects the pharmacokinetics of about 50% of the drugs in clinical use. Predictive CYP2D6 genotyping is estimated to be beneficial for treatment of about 30–40% of CYP2D6 drug substrates, that is, for about 7–10% of all drugs clinically used. 1


Individuals with IM or PM phenotype metabolize selective CYP2D6 substrates at a lower rate, and the risk for adverse drug reactions is higher. On the other hand, for prodrugs which require CYP2D6 for their activation, low or absent CYP2D6 enzymatic activity results in reduced effectiveness of drug. This is seen for the analgesic effect of tramadol and codeine. For codeine, a clear guideline is in place to recommended physician dose adjustment in various CYP2D6 phenotypes. A reduced therapeutic effect is observed in PMs for CYP2D6 in breast cancer patients receiving tamoxifen therapy and predictive pheno/genotyping driven dose adjustment is clinically valuable.1


Overall, the CYP2D6 genotype has been successfully shown to predict the clearance of, the antidepressants (desipramine, fluvoxamine, mexiletine, mianserin, nortryptiline) as well as the neuroleptics (perphenazine and zuclopenthixol) and the competitive muscarinic receptor antagonist, (tolterodine). Marked decreases in drug concentrations have been observed in UMs with tramadol, venlafaxine, morphine, mirtazapine and metoprolol. The functional impact of CYP2D6 alleles may be substrate-dependent. For example, CYP2D6*17 is generally considered as an allele with reduced function, but it displays remarkable variability in its activity towards substrates such as dextromethorphan, risperidone, codeine and haloperidol. 2