PHC5005 Chap.9 Pharmacogenetics, CYP2D6 and Phenoconversion
Pharmacogenetics, CYP2D6 and Phenoconversion
Genes as a source of drug response variability
The pharmacogenetics lecture sits in the course's block on drug response variabilities, after the pharmacokinetic and pharmacodynamic foundations.
Its outcomes are to define pharmacogenetics and distinguish it from pharmacogenomics, to show how inherited differences change whether a drug works and whether it harms, to describe real-world gene-drug interactions, and to appreciate the clinical and translational importance of pharmacogenomics in personalised medicine.
Pharmacogenetics studies genetic influences on drug response; pharmacogenomics uses genetic information to guide drug choice for an individual.
Where a variant acts
The lecture stresses that the location of a variant matters as much as its presence.
Variants can alter how much enzyme is expressed, change its activity so that it is reduced, increased or inactive, disrupt a splice site so that an abnormal or inactive enzyme is made, or sit in an untranslated region and affect messenger RNA stability or translation.
Allele names encode these consequences: for CYP2D6, *1 is the reference sequence, *4 carries a splice-site defect so that no functional protein is made, and *1xN is the reference sequence duplicated.
The codeine investigation
The tutorial is run as a consult on one referral in four layers. Three patients receive codeine with three outcomes: good relief, almost none, and an infant harmed through breast milk.
Codeine is a prodrug. CYP2D6 converts it to morphine, while UGT2B7 and CYP3A4 turn it into inactive codeine-6-glucuronide and norcodeine.
Students decode the alleles, call each patient's phenotype, trace the mechanism step by step from enzyme activity to receptor activation, and match predicted mechanisms to observed symptoms, noticing that not every prediction holds.
Applying the guideline
The third layer applies a table recreated for teaching and consistent with published CPIC guidance.
It links activity score to phenotype and recommendation: ultrarapid and poor metabolisers should avoid codeine in favour of a non-tramadol alternative, normal metabolisers receive standard dosing, and intermediate metabolisers receive standard dosing with an alternative considered if there is no response.
Phenoconversion
The final layer shows that a normal genotype does not guarantee a normal phenotype.
A patient taking fluoxetine, a strong CYP2D6 inhibitor, responds like a poor metaboliser; a patient on both a moderate and a strong inhibitor tests whether the effect stacks; and stopping one inhibitor raises the question of what is reversible. The genotype never changes, while the phenotype depends on the drugs a patient is taking today.
What this chapter covers
- 01
Pharmacogenetics, pharmacogenomics and personalised medicine
- 02
How the position of a variant changes enzyme expression or function
- 03
CYP2D6 allele nomenclature and phenotype calls
- 04
Codeine as a prodrug and its three metabolic routes
- 05
Guideline-based recommendations by activity score
- 06
Phenoconversion by CYP2D6 inhibitors and its reversibility
Worked example · free
Calling a phenotype and choosing an action
- 2Decode the diplotype and call the phenotype.
- 2Trace the effect on morphine formation and receptor activation.
- 2Apply the guideline recommendation.
Key terms
- Pharmacogenetics
- The study of genetic influences on drug responses.
- Pharmacogenomics
- The use of genetic information to guide the choice of drug for an individual.
- Diplotype
- The pair of alleles a person carries for a gene, such as CYP2D6 *1/*4.
- Poor Metaboliser
- A person whose enzyme variants give little or no activity, so drugs are metabolised slowly or prodrugs not activated.
- Ultrarapid Metaboliser
- A person with extra functional gene copies who metabolises a drug unusually fast.
- Phenoconversion
- A change in effective metabolic phenotype, caused by co-medication such as an enzyme inhibitor, without any change in genotype.
- Activity Score
- A numerical summary of enzyme function used to assign a metaboliser phenotype in the guideline table.
Pharmacogenetics, CYP2D6 and Phenoconversion FAQ
What is the difference between pharmacogenetics and pharmacogenomics?
Pharmacogenetics studies how genetic variation influences drug response. Pharmacogenomics goes a step further and uses genetic information to guide which drug an individual receives. Both feed personalised medicine, which considers disease genetics and pharmacogenomic factors together.
Why can codeine fail completely in some patients?
Codeine is a prodrug that relies on CYP2D6 to form morphine. A poor metaboliser with no functional CYP2D6, for example *4/*4, forms almost no morphine, so the mu-opioid receptors are barely activated and pain relief is minimal despite a standard dose.
Why is codeine risky for a breastfeeding mother who is an ultrarapid metaboliser?
Extra copies of CYP2D6 convert codeine to morphine quickly and in excess. The surplus passes into breast milk, and in the tutorial case the infant becomes drowsy, feeds poorly and develops grey-blue lips on day five. The course also lists codeine among significant-risk drugs in lactation.
Does a normal CYP2D6 genotype guarantee a normal response?
No. A strong CYP2D6 inhibitor such as fluoxetine or terbinafine can lower enzyme activity so much that a person with a normal genotype behaves like a poor metaboliser. This phenoconversion is why the current medication list belongs in every pharmacogenetic assessment.
What happens to phenoconversion when the inhibiting drug is stopped?
The genotype does not change, because it is inherited. The phenotype can move back towards the genotype-predicted state once the inhibitor has gone, which is the reversibility question the worksheet asks about a patient who finishes a course of terbinafine.
Why does the guideline say to avoid codeine at both extremes?
The poor metaboliser forms too little morphine, so codeine does not work. The ultrarapid metaboliser forms too much too quickly, so toxicity is the risk. Opposite mechanisms lead to the same recommendation: choose a non-tramadol alternative.
Exam move
Rehearse the five-step chain, enzyme activity, O-demethylation, morphine formation, receptor activation, clinical result, aloud for each patient type until you can run it without the worksheet. Then run it once more for a normal genotype on fluoxetine; if your chain changes at step one, you have understood phenoconversion.
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