Cytochrome P450 2D6

The CYP2D6 is of particular importance, because it metabolizes a wide range of commonly prescribed drugs, including antidepressants, antipsychotics, β-adrenergic blockers, and antiarrhythmics (Table 10.7). The CYP2D6 deficiency is a clinically important genetic variation of drug metabolism characterized by three phenotypes: UM, EM and PM. The PM phenotype is inherited as an autosomal recessive trait,with 5 of 30 of the known CYP2D6 gene mutations leading to either zero expression or the expression of a nonfunctional enzyme. Approximately 12 to 20% of Caucasians express the CYP2D6*4 allele, and 5% express the other CYP2D6 alleles.
Up to 34% of African Americans express the CYP2D6*17 allele, and 5% express the other CYP2D6 alleles. Up to 50% of Chinese express the CYP2D6*10 allele, and 5% express the other CYP2D6 alleles (these individuals are referred to as PM) (73,75). Conversely, the 20 to 30% of Saudi Arabians and Ethiopians who express the CYP2D6*2XN allele are known as UMs of CYP2D6 substrates, because they express excess enzyme as a result of having multicopies of the gene. Inasmuch as CYP2D6 is not inducible, individuals of Ethiopian and Saudi Arabian descent have genetically developed a different strategy to cope with the (presumed) high load of alkaloids and other substances in their diet; thus, the high expression of CYP2D6 using multiple copies of the gene. Those individuals who are deficient in CYP2D6 will be predisposed to adverse effects or drug toxicity from antidepressants or neuroleptics caused by inadequate metabolism or long half-lives, but the metabolism of pro-drugs in these patients will be ineffective because of lack of activation (e.g., codeine, which must be metabolized by O-demethylation to morphine).
Those with the UM phenotype will require a dose that is much higher than normal to attain therapeutic drug plasma concentrations (e.g., one patient required a daily dose of ~300 mg of nortryptyline to achieve therapeutic plasma levels) or a lower dose for pro-drugs that require metabolic activation. Individuals with the PM phenotype also are characterized by loss of CYP2D6 stereoselectivity in hydroxylation reactions.