PharmacologyTier 1Medical Sciences concept

CYP2D6 pharmacogenomics (poor/fast metabolisers)

Core concept

CYP2D6 is highly polymorphic and NOT inducible - phenotype is genetic, or created pharmacologically by an inhibitor
Copy number and null alleles give four phenotypes

Phenotype	Genotype	Prodrug (codeine, tramadol, tamoxifen)	Active drug (metoprolol, TCA, risperidone)
Poor (PM) ~5-10% European	Two non-functional alleles	No effect - analgesic failure	Toxicity - exaggerated effect
Intermediate	One reduced-function allele	Reduced effect	Mildly increased effect
Normal (extensive)	Two functional	Expected	Expected
Ultrarapid (UM)	Gene duplication - up to 30% in North/East African, Middle Eastern ancestry	Toxicity - rapid morphine formation	Failure - needs higher doses

The direction reverses depending on whether the drug is a prodrug - this is the whole examinable point

Codeine -> morphine by CYP2D6 (~10% of the dose)
- Ultrarapid metaboliser -> life-threatening respiratory depression; deaths in children post-tonsillectomy and in a breastfed neonate
- Poor metaboliser -> codeine simply does not work; the patient reporting "codeine does nothing" is describing a genotype
- Contraindicated under 12 years, and in breastfeeding
Tramadol - same activation to O-desmethyltramadol; same problem, plus serotonergic effect
Tamoxifen -> endoxifen by CYP2D6; avoid paroxetine and fluoxetine, use venlafaxine/citalopram/escitalopram
Metoprolol - CYP2D6 substrate; a rapid metaboliser needs higher doses, a poor metaboliser gets exaggerated bradycardia
- Bisoprolol and atenolol are not CYP2D6 dependent - a workaround
TCAs (nortriptyline, amitriptyline) and risperidone, haloperidol, aripiprazole, atomoxetine, vortioxetine are all substrates
Phenoconversion - a potent inhibitor converts a normal metaboliser into a functional poor metaboliser
- Fluoxetine, paroxetine, bupropion, duloxetine, quinidine, terbinafine
- A patient on paroxetine plus tamoxifen is phenotypically a poor metaboliser regardless of genotype
CYP2D6 accounts for ~25% of clinically used drugs despite being a small fraction of hepatic CYP protein

Reported "opioid doesn't work" or "opioid knocked me out" is a phenotype clue - and it predicts the response to other CYP2D6 drugs including metoprolol
Practical prescribing responses
- Analgesia -> use an opioid not requiring activation: oxycodone (partly), morphine, hydromorphone, fentanyl, buprenorphine
- Hot flushes on tamoxifen -> venlafaxine, never paroxetine
- Beta-blockade with a known interaction -> bisoprolol
Genotype testing is available and used routinely in some settings (psychiatry, oncology), but the drug history usually gives the phenotype for free
Not all pharmacogenomics is CYP - contrast the transferase examples: TPMT/NUDT15 (azathioprine), DPYD (fluoropyrimidines), UGT1A1 (irinotecan), G6PD (rasburicase, primaquine), HLA alleles (immunological, not metabolic)

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