CYP2D6-polymorphism

Known genetic polymorphism of the cytochrome P450-dependent monooxygenase CYP2D6. Cytochrome P450 isoenzyme 2D6 (CYP2D6) is involved in the metabolism of about 25% l of the most common drugs, particularly psychotropic drugs of the SSRI (serotonin reuptake inhibitor) type, beta-blockers and analgesics.

The different CYP2D6 genotypes and phenotypes show a marked geographical clustering . In northern Europe, slow metabolizers are found more frequently. In the Mediterranean region and in parts of Africa, the "ultrafast metabolizers" are found in 10 to 20%, which is explained by an advantage in the utilization of vegetarian (alkaloid-containing) food.

The elimination rate of CYP2D6 substrates can differ by a factor of up to 100 Basically, four types are distinguished with regard to the metabolisation activity of CYP2D6:

1. Poor metabolizers (PM) possess two non-functional alleles. Thus, no CYP2D6 is produced. The metabolism of a drug is extremely slow. Accumulation is to be expected even at standard doses. Above-average plasma levels are the consequence with increased side effects, intoxications and interactions. In contrast, a prodrug that is activated by CYP2D6 will not achieve adequate drug levels.
2. Intermediate metabolizers (IM) either have two gene copies coding for an enzyme with reduced activity (homozygous) or one normal and one dysfunctional allele (heterozygous). Pharmaceuticals are therefore only metabolized with reduced activity.
3. Extensive (normal) metabolizers (EM) are homozygous for the wild-type allele (normal allele form). Fully functional CYP2D6 proteins are formed at physiological levels. Drugs are metabolized efficiently in this phenotype, and the drug effect is as expected for a standard dose.
4. Ultrarapid metabolizers (UM) have 3 or more copies of functional alleles due to gene amplification. Affected patients metabolize drugs so rapidly that effective plasma levels cannot be achieved or can only be achieved for a short time. These patients do not respond or only respond insufficiently to pharmacotherapy even after administration of very high doses. When a prodrug is administered, on the other hand, so much of the active substance is formed per unit of time that toxic concentrations can be reached or undesirable drug effects occur.

Therapeutically relevant is the CYP2D6 polymorphism in the treatment with class I antiarrhythmics, beta-blockers, neuroleptics and antidepressants, which (if they are CYP2D6 substrates) lead to higher plasma levels in the slow metabolizer, with pronounced side effects. Codeine and tramadol are inhibited in their bioactivation in the slow metabolizer. In ultrafast metabolizers, on the other hand, significantly more morphine is formed from codeine. This is particularly important in children.