3 Clinical psychopharmacology3.2 Pharmacokinetics
3.2.1.6 The CYP450 system
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Written by Resident Doctor Committee · Published
The enzyme system
Cytochrome P450 (CYP) enzymes are haem-containing proteins that carry out phase I oxidation (hydroxylation, dealkylation) of most psychotropic drugs in the liver and gut wall.
The drug-metabolising enzymes sit in the smooth endoplasmic reticulum of hepatocytes.
Inhibition of an enzyme usually raises exposure to an active parent drug, and induction usually lowers it.
The number of functional allele copies predicts metaboliser phenotype.
Functional copies | Phenotype |
|---|---|
None | Poor |
One | Intermediate |
Two | Normal (extensive) |
More than two | Ultrarapid |
CYP2D6
CYP2D6 encodes debrisoquine hydroxylase, a highly polymorphic phase I enzyme.
It metabolises the widest range of antidepressants and shows the widest variation between individuals of any P450, from poor to ultrarapid metabolisers.
Roughly 5 to 10% of people of white European ancestry are poor metabolisers with no functional enzyme.
Risperidone is cleared mainly by CYP2D6 9-hydroxylation, which forms active paliperidone.
Donepezil is cleared by both CYP2D6 and CYP3A4, so an inhibitor of either can raise its level.
Antidepressants that inhibit CYP2D6
Fluoxetine (with its metabolite norfluoxetine) and paroxetine are potent CYP2D6 inhibitors, so co-prescribed CYP2D6 substrates accumulate; most other antidepressants inhibit it weakly or not at all.
Paroxetine inhibits the isoenzyme that clears it, so its plasma levels rise out of proportion to dose.
Citalopram and escitalopram are only weak inhibitors of hepatic CYP450 enzymes, unlike paroxetine, fluvoxamine, bupropion and duloxetine.
Other isoenzymes
Isoenzyme | Psychotropic substrates | Inhibitors | Inducers |
|---|---|---|---|
CYP1A2 | Olanzapine (chief route), clozapine, duloxetine | Fluvoxamine (potent), ciprofloxacin | Tobacco smoke |
CYP2C19 | Citalopram, escitalopram, diazepam | Fluvoxamine, omeprazole | Carbamazepine, rifampicin |
CYP3A4 | Quetiapine, aripiprazole, donepezil | Grapefruit juice, ketoconazole, clarithromycin | Carbamazepine, phenytoin, rifampicin, St John's wort |
Grapefruit juice inhibits intestinal CYP3A4 and raises levels of drugs it clears; a drug not metabolised by P450, such as pregabalin, is spared.
Lithium is excreted unchanged by the kidney, so P450 inhibition or induction does not alter its metabolism.
Induction and inhibition
Strong inducers of hepatic CYP450 enzymes are carbamazepine, phenytoin, phenobarbital, rifampicin and St John's wort.
Valproate inhibits hepatic CYP450 enzymes, the opposite of carbamazepine.
A selective serotonin reuptake inhibitor (SSRI) that interferes with P450 metabolism, such as fluvoxamine, does so by inhibition.
Carbamazepine is both a substrate and an inducer of CYP3A4, so it induces its own metabolism (autoinduction) and its clearance rises over the first weeks of regular dosing.
Induction develops over days to weeks, and when an inducer is stopped, substrate levels rise again as the enzyme turns over.
Tobacco and cannabis smoke
Polycyclic aromatic hydrocarbons in tobacco and cannabis smoke induce hepatic CYP1A2 (and CYP2E1), lowering levels of drugs cleared by that route.
Nicotine itself does not induce CYP1A2, so nicotine replacement does not keep levels down.
The smoking effect on antipsychotic levels runs through CYP1A2, not CYP2D6.
Stopping smoking can raise clozapine levels within days, and infection can raise them further.