Savvy Psychopharmacology Making sense of CYP2D6 and CYP1A2 genotype vs phenotype O. Greg Deardorff, PharmD, BCPP, Victoria Jenne, PharmD, MPH, BCPS, and Lauren Leonard, PharmD he clinical response to the same dose Phenoconversion occurs when these factors of a drug may vary among individu- result in a phenotype that is different from T als. Cytochrome P450 (CYP) 2D6 and that predicted by genotype. Because of the 1A2 are enzymes that metabolize many possibility of phenoconversion, knowing a psychotropic medications. Genetic varia- patient’s genotype may be of limited value tions in these enzymes may cause changes in making clinical decisions. This article in their activity and result in differences in provides guidance on interpreting both the Vicki L. Ellingrod, effectiveness and adverse effects. Although genotype and phenotype of CYP2D6 and PharmD, FCCP pharmacogenetic testing is available for CYP1A2. For 2 case reports that illustrate the Department Editor CYP2D6 and CYP1A2, interpretation and concepts discussed, see the online version of clinical application of the results may not be this article at MDedge.com/psychiatry. straightforward. Genetic variations in CYP450 enzymes CYP2D6 determine enzymatic activity, which can The enzyme activity of CYP2D6 varies have a large effect on drug levels, efficacy, among individuals and may include no and toxicity. However, there are many other activity, decreased activity, normal activ- important factors that clinicians should con- ity, or increased activity. After obtaining the sider when trying to predict the effects of genotype, the activity level of the CYP2D6 medications. While clinicians often focus alleles may be determined. The frequency on a patient’s genotype, this only provides with which certain alleles occur varies with information on a chromosomal level, and ancestry. More than 100 allelic variants and this information never changes. In contrast, subvariants have been discovered, and new a patient’s phenotype, or status of metabo- alleles are continuing to be discovered.1 lism, is subject to change throughout the continued patient’s life. Practice Points Many circumstances influence phe- • Unlike most other CYP450 enzymes, notype, including the use of medications CYP2D6 is not very susceptible to that induce or inhibit CYP450 enzymes, enzyme induction. Therefore, genetics, environmental factors, and comorbidities. rather than drug therapy, accounts for most ultra-rapid CYP2D6 metabolizers. Savvy Psychopharmacology is produced in partnership Dr. Deardorff is Clinical Manager, Fulton State Hospital, Fulton, Missouri; • When using multiple medications that are with the College of Psychiatric Adjunct Clinical Assistant Professor, University of Missouri-Kansas City substrates and/or inhibitors of CYP2D6, School of Pharmacy, Kansas City, Missouri; Adjunct Clinical Faculty, St. and Neurologic Louis College of Pharmacy, St. Louis, Missouri; and Adjunct Clinical genotyping may not reflect the true Pharmacists Faculty, University of Missouri School of Medicine, Columbia, Missouri. prevalence of the CYP2D6 poor cpnp.org Dr. Jenne is a Clinical Pharmacist, and Dr. Leonard is a Pharmacy metabolizer phenotype. mhc.cpnp.org (journal) Manager, St. Louis Psychiatric Rehabilitation Center, St. Louis, Missouri. Disclosures • The activity of CYP1A2 alleles is The authors report no financial relationships with any company whose largely determined by environmental products are mentioned in this article or with the manufacturers of factors and genetic variability. Current Psychiatry competing products. Vol. 17, No. 7 41 Savvy Psychopharmacology Table 1 a phenotype that does not correspond CYP2D6 allele activity to genotype. Allele Activity level *1 Normal Phenoconversion Genotyping may not reflect the true preva- *2A Increased lence of the CYP2D6 poor metabolizer phe- *2B Decreased notype when using multiple medications *2D Decreased that are substrates and/or inhibitors of *3 None CYP2D6.8 In the presence of strong CYP2D6 *4 None inhibitors, up to 80% of individuals with a *5 None non-poor metabolizer genotype are con- *6 None verted to a poor metabolizer phenotype.8 Clinical Point *7 None While the phenotype provides a clearer *8 None Unlike most other representation of metabolism status than *9 Decreased genotype, this information may not always CYP450 enzymes, *10 Decreased be available. CYP2D6 is not *11 None very susceptible to *15 None Determining CYP2D6 phenotype enzyme induction *17 Decreased Risperidone and venlafaxine levels are *41 Decreased useful tools for predicting CYP2D6 phe- Source: Adapted from reference 2 notype.3,8 When a risperidone level is ordered, the results include a risperidone level and a 9-hydroxyrisperidone level. The active metabolite of risperidone is Table 12 lists some of the most common 9-hydroxyrisperidone (paliperidone). CYP2D6 alleles. The risperidone-to-9-hydroxyrisperidone Based on the CYP2D6 enzyme activity (R-to-9-OHR) concentration ratio is an determined from the alleles, 4 “traditional” indicator of CYP2D6 phenotype.3 While phenotypes can be predicted from the gen- considerable overlap may exist using otype (Table 2,2 page 43). The 7-category R-to-9-OHR concentration ratios as a phenotypes reported by some laboratory predictor of CYP2D6 phenotype, this pro- companies provide a more explicit method vides a practical and economically viable for reporting phenotypes. option for guiding drug therapy and Evidence suggests that, unlike most recommending CYP2D6 genetic testing. other CYP450 enzymes, CYP2D6 is not very The median R-to-9-OHR concentration susceptible to enzyme induction.2 Thus, ratios with the 25th to 75th percentiles genetics, rather than drug therapy, accounts are listed below as indicators of CYP2D6 for most ultra-rapid CYP2D6 metaboliz- phenotypes9: ers. CYP2D6 can be inhibited by the use • Ultra-rapid metabolizer: 0.03 (0.02 of medications (Table 3,2-5 page 43) and/ to 0.06) or substrates (Table 4,2,6 page 44). Similar • Extensive metabolizer: 0.08 (0.04 Discuss this article at to inhibitors, substrates may be saturating to 0.17) www.facebook.com/ high affinity-low capacity enzymes such • Intermediate metabolizer: 0.56 (0.30 MDedgePsychiatry as CYP2D6, resulting in phenoconver- to 1.0) sion to poor metabolizers. However, this • Poor metabolizer: 2.5 (1.8 to 4.1). is unlikely to be the case for substrates Although a R-to-9-OHR concentration ratio of low affinity-high capacity enzymes such >1 generally indicates a poor metabolizer, it as CYP3A4.7 Ultimately, substrates and/ could also indicate the presence of a power- Current Psychiatry 42 July 2018 or inhibitors of CYP2D6 may result in ful CYP2D6 inhibitor.9 Savvy Psychopharmacology Table 2 CYP2D6 enzyme activity 4 traditional 7-category phenotypes phenotypes Definition Ultra-rapid Ultra-rapid >2 alleles with normal activity OR ≥2 alleles with increased activity Extensive Enhanced 1 allele with increased activity and 1 allele with normal activity extensive Extensive 2 normal activity alleles OR 1 allele with increased activity and 1 allele with decreased activity Intermediate Enhanced 1 increased activity allele paired with an allele with no activity Clinical Point intermediate OR 1 normal activity allele paired with an allele with decreased activity The activity of OR CYP1A2 alleles is 3 alleles with decreased activity largely determined Intermediate 1 normal activity allele paired with an allele with no activity OR by environmental 2 alleles with decreased activity factors and genetic Poor Reduced 1 allele with decreased activity paired with 1 allele with no activity variability intermediate Poor No alleles with any level of activity Source: Adapted from reference 2 Table 3 CYP2D6 inhibitors Weak inhibitors Moderate inhibitors Strong inhibitors Antidepressants Sertraline Fluoxetine — Duloxetine Paroxetine — Bupropion — Antipsychotics Asenapine — Thioridazine — Perphenazine Miscellaneous Diphenhydramine Terbinafine Quinidine Amiodarone — Chloroquine — — Cinacalcet — — Imatinib Source: References 2-5 When a venlafaxine level is ordered, phenotype.8 In this instance, a ratio ≥1 indi- the results include a venlafaxine level cates an extensive metabolizer, whereas <1 and an O-desmethylvenlafaxine level. indicates a poor metabolizer. O-desmethylvenlafaxine (desvenlafaxine) is the active metabolite of venlafaxine. The CYP1A2 O-desmethylvenlafaxine-to-venlafaxine While the activity of CYP2D6 alleles is Current Psychiatry concentration ratio is an indicator of CYP2D6 determined primarily by genetic factors Vol. 17, No. 7 43 Savvy Psychopharmacology Table 4 CYP2D6 substrates Primarily metabolized Substantially metabolized Minimally metabolized by CYP2D6a by CYP2D6b by CYP2D6c Antidepressants Desipramine Amitriptyline Citalopram Doxepin Bupropion Escitalopram Fluoxetine Duloxetine Fluvoxamine Nortriptyline Imipramine Sertraline Paroxetine Mirtazapine Vilazodone Venlafaxine Trazodone — Vortioxetine — — Antipsychotics Chlorpromazine Aripiprazole Clozapine Clinical Point Haloperidol Brexpiprazole Quetiapine A significant Perphenazine Iloperidone Ziprasidone increase in caffeine Risperidone Olanzapine — Thioridazine Pimavanserin — consumption can aMain form of metabolism. Other enzymes are not involved or negligibly involved. result in CYP1A2 bInvolves most of the metabolism, but other CYP enzymes may contribute. inhibition cInvolves a slight role in metabolism and a secondary pathway to a different primary CYP enzyme exists. Source: References 2,6 Table 5 CYP1A2 allele activity level genotype–phenotype