EBM Consult

What Medications are Likely to be Influenced by the Genetic Polymorphisms to CYP2D6?


  • The normal (or wild-type) CYP2D6 enzyme activity is highly functional and efficient, which is why these patients are labeled as extensive metabolizers.
  • The majority of genetic polymorphisms to the CYP2D6 gene result in either absent or decreased function of the enzyme activity, with CYP2D6*2xn being the only one that increases its activity.
  • The two patient populations that are likely at the greatest risk for being a CYP2D6 poor metabolizer include African Americans/Black Africans and Asians.
  • The drug classes that appear to be impacted most are the psychotropics (specifically antidepressants and antipsychotics/dopamine antagonists) and/or medications known to the central nervous system (more commonly opioid analgesics).
  • The next most common type of medications known to be substrates of CYP2D6, include two cardiovascular drug classes.  These are the antihypertensives (specifically the beta-blockers) and antiarrhythmics.

Editor-in-Chief: Anthony J. Busti, MD, PharmD, FNLA, FAHA
Last Reviewed: August 2015


  • As a summary of the main genetic polymorphisms of cytochrome P450 (CYP) 2D6 and the impact those polymorphic variations have on CYP2D6 activity it is important to consider the following: 1) The normal (or wild-type) CYP2D6 enzyme activity is highly functional and efficient, which is why most patients in the population are labeled as ultra-rapid or extensive metabolizers; 2) The majority of genetic polymorphisms to the CYP2D6 gene result in either absent or decreased function of the enzyme activity (i.e., being a "poor metabolizer"); 3) The two patient populations that are likely at the greatest risk for being a CYP2D6 poor metabolizer include African Americans/Black Africans and Asians.2-18

    Given that the majority of genetic polymorphisms to CYP2D6 result in absent or reduced enzyme activity, any medication that is a substrate for metabolism and/or elimination through this pathway may have a different or unexpected change in its pharmacokinetic profile.  In many situations, a substrate of CYP2D6 is likely to result in elevated plasma concentrations which can further increase the risk for an exaggerated pharmacologic effect or side effect profile.  Furthermore, some medication substrates of CYP2D6 may require the presence of a functional enzyme in order to become activated in order for it to exert a pharmacologic effect.  A good example of this later situation can be seen with codeine and hydrocodone, where they require metabolism via CYP2D6 to their active forms (which is morphine for codeine and hydromorphone for hydrocodone).  Therefore, a nonfunctional or less active CYP2D6 can result in a reduced analgesic effect if either one of these two opioid analgesics are used for pain management. 

    Now that we have summarized the main effects of genetic polymorphisms on CYP2D6 enzyme activity and their basic effect on the pharmacokinetic profile of some medication substrates, let us now review some of the common medications used in clinical practice that may be affected.  The drug classes that appear to be impacted most are the psychotropics and/or medications known to affect the central nervous system (CNS).  The two drug classes making up the psychotropics include the antidepressants and antipsychotics/dopamine antagonists.  The antidepressants that are known substrates of CYP2D6 include amitriptyline, clomipramine, desipramine, duloxetine, fluoxetine, fluvoxamine, imipramine, mirtazapine, nortriptyline, paroxetine, sertraline, and venlafaxine.  The CYP2D6 substrates making up the antipsychotics/dopamine antagonists include aripiprazole, clozapine, fluphenazine, haloperidol, metoclopramide, olanzapine, perphenazine, quetiapine, risperidone, and thioridazine. Other drug classes and medications that affect the CNS include acetylcholinesterase inhibitors (donepezil, galantamine); antihistamines (chlorpheniramine); muscle relaxants (cyclobenzaprine); norepinephrine reuptake inhibitor (atomoxetine); and opioid analgesics (codeine, hydrocodone, meperidine, methadone, morphine, oxycodone, and propoxyphene). 

    The next most common group of medications known to be substrates of CYP2D6 include two cardiovascular drug classes.  The first of these are antihypertensives and specifically the beta-blockers.  The beta-blockers include bisoprolol, carvedilol, metoprolol, nebivolol, and propranolol.  The second class includes antiarrhythmic medications such as flecainide, lidocaine, mexiletine, propafenone, and quinidine.  Lastly, the other remaining medication substrates that are worth mentioning include cinacalcet, dextromethorphan, dolasetron, ondansetron, ritonavir, tamoxifen, and tolterodine.

    The recognition of these various medications are of clinical relevance since 34% of the listed medications also represent medications in the most recent Top 200 Drug List published.19  Due to their wide spread use, it is plausible that they will be used in patients with an unknown genetic polymorphism to CYP2D6 and result in unexpected pharmacologic effects.  For a comprehensive list of medications substrates of CYP2D6, please visit the drug tables on the website.


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MESH Terms & Keywords

  • CYP2D6 Genetic Polymorphisms, Medication Substrates of CYP2D6