What Drugs Are Metabolized by CYP2D6?

CYP2D6 is one of the liver’s main drug-processing enzymes, and it handles over a quarter of commonly prescribed medicines, along with most heart-rhythm drugs.1PubMed Central. Cytochrome P450-2D6 Genotype Definition May Improve Therapy for Paroxysmal Atrial Fibrillation A Case of Syncope Following “Pill-in-the-Pocket” Quinidine plus Propafenone How well the enzyme works differs from person to person because of the genes you inherit, so it can decide whether a standard dose is right, weak, or too strong for you.

Common Medicines That CYP2D6 Breaks Down

The enzyme recognizes the general chemical shape of a molecule, not what the drug is for, so an antidepressant and a heart-rhythm drug can both fit. Two of them taken together can compete and slow each other down, which is the root of the interactions covered later.

Sharing the enzyme doesn’t mean depending on it equally. Some drugs rely on CYP2D6 mainly, while others share the work with a second enzyme, as risperidone and aripiprazole do with CYP3A4.14PubMed. Metabolic drug interactions with newer antipsychotics: a comparative review A weak CYP2D6 therefore matters most for drugs that have no other main route out of the body.

To see whether your own medicine is affected, match the generic name, the active ingredient printed on the box or pharmacy label, against any list. Cough and cold products deserve a second look, because dextromethorphan can sit in the small print of a multi-symptom remedy rather than on the front. The list above covers well-known examples, not every drug the enzyme touches, so a drug missing from it may still use CYP2D6. A pharmacist can run your whole list, including over-the-counter products and supplements, through an interaction checker in a few minutes, usually at no cost.

Drugs That Need CYP2D6 to Work at All

Most drugs on the list are cleared by the enzyme, but a few are activated by it. Codeine itself is weak; CYP2D6 converts it into morphine, which does the pain relief.15PubMed Central. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype How well codeine works and how safe it is therefore depend on your version of the enzyme.16PubMed Central. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype Tramadol is activated the same way, into a stronger pain-relieving form.17PubMed. Developmental pharmacology of tramadol during infancy: ontogeny, pharmacogenetics and elimination clearance

That creates two opposite risks. With too little enzyme, a drug that must be activated may barely work, so someone taking codeine can get little relief even at the full dose. With a lot of enzyme, codeine turns into morphine faster than expected, and an ordinary dose can bring overdose-like effects such as extreme drowsiness or slowed breathing. Drugs the enzyme simply clears behave the other way round: low enzyme makes them build up, and high enzyme can make them wear off too quickly.

Tamoxifen depends on the enzyme for its benefit. It becomes effective after the liver turns it into endoxifen, with CYP2D6 doing most of that step.18PubMed. CYP2D6 and tamoxifen: DNA matters in breast cancer19PubMed Central. Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen People with low enzyme activity make little endoxifen and seem to get less benefit from tamoxifen.20PubMed. CYP2D6 and tamoxifen: DNA matters in breast cancer The version of the enzyme someone carries explains much, but not all, of how much endoxifen they make.21PubMed Central. Improved Prediction of Endoxifen Metabolism by CYP2D6 Genotype in Breast Cancer Patients Treated with Tamoxifen

If you take tamoxifen, ask your oncologist or pharmacist whether any other medicine you use, especially an antidepressant, blocks the enzyme, since that could reduce how much endoxifen you make. Don’t stop or change tamoxifen on your own; interrupting cancer treatment is a bigger risk than any worry about the enzyme. If you have a genetic report, bring it along so it can be read next to your full medicine list.

What Happens to Cleared Drugs When the Enzyme Is Slow

In people with no working CYP2D6, atomoxetine lingers about three times longer, with a half-life of about 62 hours versus 18.22PubMed. Disposition and metabolic fate of atomoxetine hydrochloride: the role of CYP2D6 in human disposition and metabolism Each daily dose lands on top of leftover drug, so levels can build over days and side effects may arrive gradually rather than from the first tablet.

Heart-rhythm drugs show the same spread. Blood levels vary widely at normal doses, largely because of differences in this enzyme.23PubMed Central. Cytochrome P450-2D6 Genotype Definition May Improve Therapy for Paroxysmal Atrial Fibrillation A Case of Syncope Following “Pill-in-the-Pocket” Quinidine plus Propafenone For tricyclic antidepressants, people with the weakest enzyme often need about half the usual dose.24PubMed Central. The pharmacogenetics of CYP2D6 and CYP2C19 in a case series of antidepressant responses25PubMed Central. Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2D6 and CYP2C19 Genotypes and Dosing of Tricyclic Antidepressants: 2016 Update

Buildup can feel different depending on the drug. With tricyclics, it can show up as drowsiness, a dry mouth and dizziness when you stand up. With beta-blockers such as metoprolol, look for an unusually slow pulse or unusual tiredness. With heart-rhythm drugs, lightheadedness or fainting needs urgent medical attention, not a wait-and-see approach. If effects seem stronger than the leaflet describes, report them to your prescriber, since that is exactly the pattern a slow enzyme can produce. Side effects alone don’t prove your enzyme is slow, because many other things cause them, but they are a reason to ask.

Reading Your CYP2D6 Result

Reports sort people into four groups: poor, intermediate, normal and ultrarapid metabolizers.26GeNotes. Pharmacogenomics of CYP2D6 A poor metabolizer has little or no working enzyme, so cleared drugs stay longer and drugs that need activating may not work. An ultrarapid metabolizer has more activity than usual, often from extra gene copies, so cleared drugs may leave fast and activated drugs may form too quickly.

Each gene copy you carry gets a value, and the two add up to an activity score.27GeNotes. Pharmacogenomics of CYP2D6 A score of 0 means poor, scores up to 1 mean intermediate, about 1.25 to 2.25 normal, and above 2.25 ultrarapid.28Clinical Pharmacology & Therapeutics. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy Some labs draw the lines a little differently, so read your report’s own key.

Genes are written in star codes such as *1/*4, one code for each of the two copies you inherited. *1 is the standard, fully working version, and other numbers mark versions with reduced or no function, or extra copies. After the codes, the report states a predicted group, and that line is the one that matters for your medicines. Keep a copy: your inherited genes don’t change over your life, so the result can be reused for any future prescriber.

Most people, about 67 to 90% depending on ancestry, are normal metabolizers.29PubMed Central. Prediction of CYP2D6 phenotype from genotype across world populations About 0.4 to 5.4% are poor metabolizers, and 1 to 21% ultrarapid.30PubMed Central. Prediction of CYP2D6 phenotype from genotype across world populations In Europe, extra gene copies run from under 1% in Scandinavia to about 6% in Greece and Turkey.31PubMed Central. Frequencies of clinically important CYP2C19 and CYP2D6 alleles are graded across Europe

Being in a smaller group isn’t a disease or a sign of poor health; it matters only when you take a drug that depends on this enzyme. If your report was run for a particular drug, ask how the lab applied your group to that drug’s advice.

How Other Medicines Can Change Your Enzyme

Paroxetine and fluoxetine are strong blockers of CYP2D6, and sertraline, citalopram and fluvoxamine weaker ones.32PubMed Central. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes Fluoxetine’s breakdown product blocks it too, so its effect continues after the drug itself is gone.33PubMed Central. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes Paroxetine permanently disables enzyme copies, so the body must build new ones, which takes days.34PubMed. Apparent mechanism-based inhibition of human CYP2D6 in vitro by paroxetine: comparison with fluoxetine and quinidine35PubMed. In vitro-in vivo extrapolation of CYP2D6 inactivation by paroxetine: prediction of nonstationary pharmacokinetics and drug interaction magnitude

A medicine can make you act like a different group than your genes say.36PubMed Central. CYP2D6 pharmacogenetics and phenoconversion in personalized medicine On paroxetine, 94% of people with one weak gene copy behaved like poor metabolizers, versus 56% with two working copies.37PubMed. Impact of CYP2D6 Functional Allelic Variations on Phenoconversion and Drug-Drug Interactions A “normal” gene result can therefore be wrong in practice while you take a blocker.

Some combinations are worth asking about. Paroxetine or fluoxetine taken with codeine or tramadol can leave pain poorly controlled, because the blocked enzyme cannot activate the painkiller. The same antidepressants with tamoxifen may lower its benefit by cutting how much endoxifen the body makes. With metoprolol, they can slow the pulse more than expected, since less of the beta-blocker is cleared. The effect can last a while after you stop fluoxetine or paroxetine, so the timing of a new prescription matters as well as the combination.

Tell every prescriber everything you take, including over-the-counter products such as cough medicine, since dextromethorphan depends on this enzyme. Pharmacy software flags many risky pairs but not all, so your own list is a useful second check, and using one pharmacy where possible lets that pharmacist see everything at once.

What to Do If You Take a CYP2D6 Medicine

For pain medicines, normal and intermediate metabolizers can usually start codeine or tramadol at the usual dose, with intermediates watched for weak relief.38Clinical Pharmacology & Therapeutics. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy Poor metabolizers should avoid both, because they’re unlikely to work and higher doses aren’t advised.39Clinical Pharmacology & Therapeutics. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy Ultrarapid metabolizers should not use them either, to avoid severe toxicity.40Clinical Pharmacology & Therapeutics. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy Non-opioid painkillers or opioids not processed by CYP2D6 are the alternatives.41Clinical Pharmacology & Therapeutics. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy For nausea, ultrarapid metabolizers may clear ondansetron-type drugs too fast, so granisetron, which doesn’t use this enzyme, can be offered instead.42PubMed Central. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 Genotype and Use of 5‐HT3 Receptor Antagonists: 2026 Update

If your result points away from a medicine you take, don’t stop it on your own; contact your prescriber or pharmacist first. Ask whether the plan is to keep the drug, adjust the dose or switch, since guidelines allow each depending on your group.

Before surgery or a dental procedure, tell the team your metabolizer group early, ideally before the day itself, so they can plan. Ask what pain medicine is planned for home, because codeine and tramadol are common prescriptions afterward. If you are ultrarapid, ask about the anti-nausea drug, since ondansetron may work less well for you.

Children need extra care. Babies process tramadol differently as their kidneys and liver mature, so how a dose behaves can change in the early months. Ask a doctor before giving any codeine or tramadol product to a child, including ones bought without a prescription. Ultrarapid children face the same toxicity risk as ultrarapid adults, and a child can’t always describe the early signs. Unusual sleepiness or slow breathing after a dose needs urgent medical help.