CYP2D6 Interactions

## The CYP2D6 Enzyme

CYP2D6 accounts for only 2-5% of hepatic CYP content yet metabolizes approximately 25% of clinically used drugs, including many antidepressants, antipsychotics, opioids, and beta-blockers. Uniquely, CYP2D6 is not meaningfully inducible, so interactions are driven primarily by inhibition and genetic variation.

## Genetic Polymorphism

CYP2D6 is the most polymorphic drug-metabolizing enzyme. Four metabolizer phenotypes are recognized:

- **Poor metabolizers (PM)** — 5-10% of Caucasians carry two non-functional alleles (e.g., *3, *4, *5). They experience dramatically elevated substrate levels.
- **Intermediate metabolizers (IM)** — reduced but not absent activity
- **Normal metabolizers (NM)** — two functional alleles
- **Ultrarapid metabolizers (UM)** — gene duplications (CYP2D6*1xN or *2xN), common in East Africa and the Middle East. Prodrugs like codeine are activated too rapidly, causing toxicity.

## Key CYP2D6 Inhibitors

Since CYP2D6 cannot be induced, inhibition is the primary drug interaction concern:

- **Fluoxetine and paroxetine** — potent inhibitors; converting a normal metabolizer to a phenotypic poor metabolizer. Fluoxetine's active metabolite norfluoxetine inhibits CYP2D6 for weeks after discontinuation.
- **Bupropion** — strong inhibitor often overlooked in smoking cessation and depression therapy
- **Quinidine** — the prototype CYP2D6 inhibitor at sub-antiarrhythmic doses
- **Terbinafine** — antifungal with prolonged inhibition (weeks after stopping)

## High-Risk Interactions

### Tamoxifen and CYP2D6 Inhibitors

Tamoxifen requires CYP2D6 activation to its potent metabolite endoxifen. Concomitant paroxetine or fluoxetine reduces endoxifen formation by 50-75%, potentially compromising breast cancer treatment. The NCCN recommends avoiding strong CYP2D6 inhibitors in tamoxifen-treated patients.

### Codeine in Ultrarapid Metabolizers

CYP2D6 converts codeine to morphine. Ultrarapid metabolizers generate excessive morphine, causing respiratory depression. Fatal cases in breastfeeding infants prompted FDA black box warnings and contraindication of codeine in children under 12.

### Metoprolol Accumulation

Metoprolol is extensively metabolized by CYP2D6. Adding fluoxetine can increase metoprolol AUC 4-8 fold, causing severe bradycardia and hypotension.

## Clinical Management

Pharmacogenomic testing for CYP2D6 is recommended before initiating tamoxifen, codeine, or tramadol by CPIC guidelines. When prescribing a CYP2D6 inhibitor alongside a substrate, consider alternatives: citalopram or sertraline instead of paroxetine with tamoxifen; atenolol instead of metoprolol with fluoxetine.

## Key Takeaways

- CYP2D6 is not inducible; inhibition and genetics drive all significant interactions
- 5-10% of Caucasians are poor metabolizers with dramatically altered drug response
- Fluoxetine, paroxetine, and bupropion are potent CYP2D6 inhibitors
- Tamoxifen efficacy is compromised by CYP2D6 inhibition — avoid paroxetine and fluoxetine
- Codeine is contraindicated in CYP2D6 ultrarapid metabolizers due to fatal morphine toxicity risk