3 Clinical psychopharmacology3.2 Pharmacokinetics
3.2.5 Pharmacogenomics and pharmacogenetics
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Written by Resident Doctor Committee · Published
Definitions
Pharmacogenetics studies how variants in single genes affect drug response.
Pharmacogenomics studies variation across the whole genome.
Genotype predicts drug exposure better than it predicts remission.
CYP2D6 metaboliser phenotypes
CYP2D6 metabolises many tricyclics, risperidone, aripiprazole, haloperidol, venlafaxine and atomoxetine.
Phenotype | Enzyme activity | Effect on an active drug |
|---|---|---|
Poor | Essentially absent | High plasma levels, dose-related toxicity at standard doses |
Intermediate | Reduced | Moderately higher levels |
Normal | Reference | Population average |
Ultra-rapid | Increased, usually a gene duplication | Low levels, possible non-response |
Prodrugs show the reverse pattern, because CYP2D6 makes the active drug: poor metabolisers get little effect and ultra-rapid metabolisers get too much.
Codeine is a prodrug that CYP2D6 activates to morphine, so poor metabolisers get little analgesia. Ultra-rapid metabolisers risk morphine toxicity, including fatal respiratory depression in children after tonsillectomy.
Ethnicity
Asian patients usually need lower antipsychotic doses than White European patients, partly because of CYP450 differences, though ancestry alone cannot set an individual's dose.
Lithium is cleared unchanged by the kidney, so its pharmacokinetics do not vary between ethnic groups. Its clearance depends on renal function, sodium balance and interacting drugs.
Other enzymes
N-acetyltransferase 2 (NAT2) polymorphism makes people slow or fast acetylators, which alters the clearance of nitrazepam, isoniazid and hydralazine.
Slow acetylators clear nitrazepam slowly and have next-day sedation.
CYP1A2 metabolises clozapine and olanzapine. The hydrocarbons in tobacco smoke induce it, not nicotine.
When people stop smoking, clozapine levels can rise sharply within days, even if they use nicotine replacement.
Alcohol
Alcohol dehydrogenase (ADH) turns alcohol into acetaldehyde, and aldehyde dehydrogenase (ALDH) clears it.
Variant | Effect | Frequency |
|---|---|---|
ADH1B*1 | Lower activity | 85 to 95% of White Europeans are homozygous |
ADH1B*2 | High activity, fast acetaldehyde formation | Common in East Asians, uncommon in White Europeans |
ALDH2*2 | Inherited ALDH deficiency, slow acetaldehyde clearance | Common in East Asians |
Both ADH1B*2 and ALDH2*2 let acetaldehyde build up after drinking. This causes an aversive flush with tachycardia and nausea, which lowers the risk of dependence.
Disulfiram causes the same flush by inhibiting aldehyde dehydrogenase.
Genes and their proteins
The SLC6 family encodes sodium-dependent monoamine transporters.
Gene | Product | What to know |
|---|---|---|
SLC6A2 | Noradrenaline transporter | Atomoxetine and reboxetine block it |
SLC6A3 | Dopamine transporter | Methylphenidate blocks it, raising striatal dopamine; its 40-base-pair repeat variant is the most studied in attention deficit hyperactivity disorder |
SLC6A4 | Serotonin transporter | Promoter length polymorphism |
COMT | Catechol-O-methyltransferase | Breaks down prefrontal dopamine |
COMT lies on chromosome 22q11, the region lost in 22q11.2 deletion syndrome.
The methionine allele of the Val158Met polymorphism gives a less active enzyme.
COMT shapes prefrontal dopamine because the cortex has few dopamine transporters.
Genetic testing in practice
Duffy-null variants in ACKR1 give a lower but healthy neutrophil count, mainly in people of African or Middle Eastern ancestry.
Duffy-null genotyping has an agreed place in these patients when they take clozapine, because their low count can be mistaken for clozapine-induced neutropenia. It cannot exclude true neutropenia.
HLA-B*15:02 strongly raises the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis with carbamazepine. People of Han Chinese, Thai and other South East Asian ancestry are tested before they start it.
UK practice does not support routine CYP2D6 or CYP2C19 testing before a first antidepressant.