CYP2D6 pharmacogenetics and phenoconversion in personalized medicine

ABSTRACT

Introduction

CYP2D6 contributes to the metabolism of approximately 20–25% of drugs. However, CYP2D6 is highly polymorphic and different alleles can lead to impacts ranging from null to increase in activity. Moreover, there are commonly used drugs that potently inhibit the CYP2D6, thus causing ‘phenoconversion’ which can convert the genotypic normal metabolizer into phenotypic poor metabolizer. Despite growing literature on the clinical implications of non-normal CYP2D6 genotype and phenoconversion on patient-related outcomes, implementation of CYP2D6 pharmacogenetics and phenoconversion to guide prescribing is rare. This review focuses on providing the clinical importance of CYP2D6 pharmacogenetics and phenoconversion in precision medicine and summarizes the challenges and approaches to implement these into clinical practice.

Areas covered

A literature search was performed using PubMed and clinical studies documenting the effects of CYP2D6 genotypes and/or CYP2D6 inhibitors on pharmacokinetics, pharmacodynamics or treatment outcomes of CYP2D6-metabolized drugs, and studies on implementation challenges and approaches.

Expert opinion

Considering the extent and impact of genetic polymorphisms of CYP2D6, phenoconversion by the comedications, and contribution of CYP2D6 in drug metabolism, CYP2D6 pharmacogenetics is essential to ensure drug safety and efficacy. Utilization of proper guidelines incorporating both CYP2D6 pharmacogenetics and phenoconversion in clinical care assists in optimizing drug therapy.

KEYWORDS:

• CYP2D6
• phenoconversion
• enzyme inhibition
• pharmacogenetics
• opioids
• antidepressants
• tamoxifen
• personalized medicine
• precision medicine
• drug–drug interaction
• drug–drug-gene interaction

Article highlights

• CYP2D6 is estimated to contribute to the metabolism of approximately 20–25% of drugs. CYP2D6 is involved not only in metabolizing active drugs into its inactive metabolites (e.g. paroxetine, aripiprazole) but also in metabolizing inactive drugs into its active metabolite including (e.g. codeine, tamoxifen). Therefore, the metabolic activity of CYP2D6 is associated with adverse drug reactions or drug ineffectiveness.

• The gene encoding CYP2D6 is highly polymorphic, and around 100 alleles of CYP2D6 with different impact on function of the encoded protein have been identified. An activity score is given to a specific allele of CYP2D6 and summing the activity scores of the two (or more) alleles leads to the diplotype activity score. Using the diplotype score, genotypic phenotype of CYP2D6 is estimated, with the resulting phenotypes including poor metabolizer (PM), intermediate metabolizer (IM), normal metabolizer (NM), and ultra-rapid metabolizer (UM).

• Strong (e.g. paroxetine, bupropion) and moderate (e.g. duloxetine, sertraline) inhibitors can also decrease the CYP2D6 activity, phenoconverting the genotypic NMs or UMs into phenotypic PMs or IMs. So, concomitant use of those drugs cannot be overlooked while predicting the CYP2D6 phenotype. Moreover, data indicate that up to 20–70% of the patients who are on CYP2D6 metabolized drugs are at risk of CYP2D6 phenoconversion by concomitant medications.

• It is important to adjust the activity score of CYP2D6 based on the use of CYP2D6 inhibitors. If the individual is taking one of the strong or moderate inhibitors concomitantly, then the genotype-based activity score should be multiplied by 0 or 0.5, respectively. Then, the actual clinical phenotype can be estimated based on the adjusted activity score.

• Pharmacogenetic-based drug therapy guidelines have been developed for at least 50 CYP2D6-metabolized drugs based on the activity of CYP2D6. Considering the importance of phenoconversion, Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines suggest incorporating the effects of CYP2D6 inhibitors while calculating the activity score of CYP2D6 for CYP2D6 metabolized opioids, tricyclic antidepressants, tamoxifen, and atomoxetine.

• There are many challenges to implementing the use of CYP2D6 pharmacogenetics and phenoconversion to guide prescribing. These include proper interpretation of genotype-based phenotype from CYP2D6 alleles or activity score, adjustment of phenotype considering the concomitant administration of CYP2D6 inhibitor medications, routinely checking of concomitant medications for phenotype adjustment, reimbursement of genetic testing costs, proper training of the clinicians, etc.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institutes of Health (U01-HG007269) to JA Johnson and an American College of Clinical Pharmacy Foundation Futures Grant to NA Nahid.