Pharmacogenetics of cytochrome P4502D6: genetic background and clinical implication

Abstract

Interindividual differences in the pharmacokinetics of a number of drugs are often due to hereditary polymorphisms of drug‐metabolizing enzymes. Most important is cytochrome P4502D6 (CYP2D6), also known as debrisoquine/sparteine hydroxylase. It catalyzes hydroxylation or demethylation of more than 20% of drugs metabolized in the human liver, such as neuroleptics, antidepressants, some β‐blockers and many others like codeine. About 7%−10% of Caucasians lack any CYP2D6 activity due to deletions and frame‐shift or splice‐site mutations of the gene. About 1%−3% of Middle‐Europeans, but up to 29% of Ethiopians display gene duplications, leading to elevated so‐called ultrarapid metabolization rates. Meanwhile there is now a much better understanding of the genetic background of poor, intermediate, extensive and ultrarapid metabolizers, enabling a more precise DNA genotyping‐based prediction of plasma levels. Since there is evidence that deteriorated drug elimination partly accounts for drug side‐effects, CYP2D6 genotyping could contribute to an individualized and therefore optimized drug therapy.