Polymorphism of Human Cytochrome P450 2D6 and Its Clinical Significance

Abstract

Cytochrome P450 (CYP) 2D6 is one of the most investigated CYPs in relation to genetic polymorphism, but accounts for only a small percentage of all hepatic CYPs (approximately 2-4%). There is a large interindividual variation in the enzyme activity of CYP2D6. The enzyme is largely non-inducible and metabolizes approximately 25% of current drugs. Typical substrates for CYP2D6 are largely lipophilic bases and include some antidepressants, antipsychotics, antiarrhythmics, antiemetics, beta-adrenoceptor antagonists (beta-blockers) and opioids. The CYP2D6 activity ranges considerably within a population and includes ultrarapid metabolizers (UMs), extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). There is a considerable variability in the CYP2D6 allele distribution among different ethnic groups, resulting in variable percentages of PMs, IMs, EMs and UMs in a given population. To date, 74 allelic variants and a series of subvariants of the CYP2D6 gene have been reported and the number of alleles is still growing. Among these are fully functional alleles, alleles with reduced function and null (non-functional) alleles, which convey a wide range of enzyme activity, from no activity to ultrarapid metabolism of substrates. As a consequence, drug adverse effects or lack of drug effect may occur if standard doses are applied. The alleles *10, *17, *36 and *41 give rise to substrate-dependent decreased activity. Null alleles of CYP2D6 do not encode a functional protein and there is no detectable residual enzymatic activity. It is clear that alleles *3, *4, *5, *6, *7, *8, *11, *12, *13, *14, *15, *16, *18, *19, *20, *21, *38, *40, *42, *44, *56 and *62 have no enzyme activity. They are responsible for the PM phenotype when present in homozygous or compound heterozygous constellations. These alleles are of clinical significance as they often cause altered drug clearance and drug response. Among the most important variants are CYP2D6*2, *3, *4, *5, *10, *17 and *41. On the other hand, the CYP2D6 gene is subject to copy number variations that are often associated with the UM phenotype. 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. The clinical consequence of the CYP2D6 polymorphism can be either occurrence of adverse drug reactions or altered drug response. Drugs that are most affected by CYP2D6 polymorphisms are commonly those in which CYP2D6 represents a substantial metabolic pathway either in the activation to form active metabolites or clearance of the agent. For example, encainide metabolites are more potent than the parent drug and thus QRS prolongation is more apparent in EMs than in PMs. In contrast, propafenone i...

The effect of dacomitinib (PF-00299804) on CYP2D6 activity in healthy volunteers who are extensive or intermediate metabolizers

“…Extensive metabolizers comprise the majority (70-80%) in European Caucasian populations [23,24], but the distribution of CYP2D6 ultrarapid, extensive, intermediate, and poor metabolizers is unequal between major ethnic groups [11,14]. For example, the incidence of poor metabolizers has been estimated at 6-10% in Caucasians [24][25][26][27] and at 0-1.2% in Asian populations [25,28,29].…”

“…The pharmacokinetic impact of the wide inter-individual variation in the enzymatic activity of CYP2D6 has been well documented for many substrates [14,30]; however, the clinical impact, with respect to therapeutic response, adverse effects and dosing of drugs metabolized by CYP2D6, is less clear. There are data to show that for agents where CYP2D6 represents a substantial metabolic pathway either in the formation of active metabolites or clearance of the drug, and polymorphisms can affect activity or lead to increased adverse effects.…”

“…Approximately 25% of commonly prescribed and clinically important drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, opioids, anti-arrhythmics, antipsychotics, and some beta-blockers, are known to be CYP2D6 substrates [11][12][13][14]. However, CYP2D6 is characterized by a wide range of inter-individual and interethnic differences in activity (resulting in poor, intermediate, extensive and ultrarapid metabolizers), which is partly accounted for by extensive genetic polymorphism [12,15].…”

Evaluation of Adherence Should Become an Integral Part of Assessment of Patients With Apparently Treatment-Resistant Hypertension

“…75 The frequency of fast or even ultrarapid metabolizers again may vary according to the ethnicity (1%-29%), leading to lower through concentrations. [76][77][78] Some angiotensin type I receptors blockers (losartan, irbesartan, candesartan) are metabolized by the polymorphic CYP2C9. 79 Finally, calcium antagonists are mainly substrates for highly polymorphic CYP3A4 3A5 enzymes.…”

Effect of 24 Cytochrome P450 2D6 Variants Found in the Chinese Population on Atomoxetine Metabolism in vitro

“…However, it accounts only for a small percentage of all hepatic CYPs, about ∼2-4% [1,2]. To date, more than 100 alleles have been identified by the Human CYP Allele Nomenclature Committee (http://www.cypalleles.ki.se/cyp2d6.htm), all of which exhibit marked genetic polymorphisms.…”