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

Summary:

  • 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

Explanation

  • 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.

    References:

    1. Busti AJ, Herrington JD, Lehew DS, Daves BJ, McKeever GC.  What are common genetic polymorphisms to cytochrome P450 (CYP) 2D6 that could impact drug metabolism?  PW Pharmacogenet Newsl 2010;2(43):171-175.
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    3. Kimura S, Umeno M, Skoda R C et al. The human debrisoquine 4-hydroxylase (CYP2D) locus: sequence and identification of the polymorphic CYP2D6 gene, a related gene, and a pseudogene.  Am J Hum Genet 1989;45:889-904. 
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    7. Gough AC, Miles JS, Spurr NK et al. Identification of the primary gene defect at the cytochrome P450 CYP2D locus.  Nature 1990;347:773-776.  
    8. Hanioka N, Kimura S, Meyer UA et al. The human CYP2D locus associated with a common genetic defect in drug oxidation: a G(1934)-to-A base change in intron 3 of a mutant CYP2D6 allele results in an aberrant 3-prime splice recognition site.  Am J Hum Genet. 1990;47:994-1001.  
    9. Gaedigk A, Blum M, Gaedigk R et al. Deletion of the entire cytochrome P450 CYP2D6 gene as a cause of impaired drug metabolism in poor metabolizers of the debrisoquine/sparteine polymorphism.  Am J Hum Genet 1991;48:943-950.  
    10. Nelson DR, Koymans L, Kamataki T et al. Cytochrome P450 superfamily: update on new sequences, gene mapping, accession numbers, and nomenclature.  Pharmacogenetics 1996;6:1-42.  
    11. Steen VM, Molven A, Aarskog NK et al.  Homologous unequal cross-over involving a 2.8 kb direct repeat as a mechanism for the generation of allelic variants of the human cytochrome P450 CYP2D6 gene.  Hum Molec Genet  1995;4:2251-2257.  
    12. Saxena R, Shaw GL, Relling MV et al. Identification of a new variant CYP2D6 allele with a single base deletion in exon 3 and its association with the poor metabolizer phenotype.  Hum Molec Genet 1994;3:923-926.  
    13. Tyndale R, Aoyama T, Broly F et al.  Identification of a new variant CYP2D6 allele lacking the codon encoding Lys-281: possible association with the poor metabolizer phenotype.  Pharmacogenetics 1991;1:26-32.  
    14. Kagimoto M, Heim M, Kagimoto K et al. Multiple mutations of the human cytochrome P450IID6 gene (CYP2D6) in poor metabolizers of debrisoquine: study of the functional significance of individual mutations by expression of chimeric genes.  J Biol Chem 1990;265:17209-17214.  
    15. Wang SL, Lai MD, Huang JD.  G169R mutation diminishes the metabolic activity of CYP2D6 in Chinese.  Drug Metab Dispos 1999;27:385-8.  
    16. Masimirembwa C, Persson I, Bertilsson L et al.  A novel mutant variant of the CYP2D6 gene (CYP2D6*17) common in a black African population: association with diminished debrisoquine hydroxylase activity.  Br J Clin Pharmacol  1996;42:713-9.  
    17. Wennerholm A, Johansson I, Hidestrand M et al.  Characterization of the CYP2D6*29 allele commonly present in a black Tanzanian population causing reduced catalytic activity.  Pharmacogenetics  2001;11:417-27.  
    18. Ikenaga Y, Fukuda T, Fukuda K et al.  The frequency of candidate alleles for CYP2D6 genotyping in the Japanese population with an additional respect to the -1584C to G substitution.  Drug Metab Pharmacokinet 2005;20:113-6. 
    19. Drug Topics. 2009 Top 200 Drugs by Total Prescriptions. Drug Topics June 17, 2010.

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MESH Terms & Keywords

  • CYP2D6 Genetic Polymorphisms, Medication Substrates of CYP2D6