The Cytochrome P450 System (CYP) is a family of heme-containing mono-oxygenases enzymes that detoxify foreign compounds (i.e. - medications and drugs) in the liver. Cytochrome P450 enzymes are responsible for most phase I reactions in the liver. Understanding the role of CYP enzymes is vital in the prescribing of psychotropic medications.
Most psychotropic medications are highly lipophilic substances and thus undergo biotransformation in the liver. The liver converts lipid soluble (non-polar) drugs into one or hydrophilic (polar) metabolites, which allows the drug to be eliminated into urine or bile. The metabolism of psychotropic drugs in the liver occurs in two steps:
CYP enzymes are classified into families and subfamilies according to similarities in their amino acid sequence. Each enzyme always starts with[1]:
CYP isoform | 1A2 | 2B6 | 2C9 | 2C19 | 2D6 | 3A4 |
---|---|---|---|---|---|---|
Summary | Plays minor role, metabolises ~5% of drugs | Along with CYP2A6, it is involved with metabolizing nicotine | Metabolizes ~20% of all drugs | - | • Metabolizes 25% of drugs • Many polymorphisms | • Metabolizes 50% of drugs • No significant polymorphisms |
Inducers | • Carbamazepine • Cigarettes! | • Carbamazepine | • Carbamazepine | • Carbamazepine[3] | • Carbamazepine | |
Inhibitors | Antidepressants • Fluvoxamine (potent inhibitor) | - | Antidepressants • Fluoxetine (moderate) • Fluvoxamine (moderate) Mood Stabilizers • Valproic acid (weak) | Antidepressants • Fluvoxamine (potent) • Fluoxetine (moderate) | Antidepressants • Fluoxetine (potent) • Paroxetine (potent) • Sertraline (weak/moderate) • Duloxetine (moderate) • Bupropion (moderate) Antipsychotics • Perphenazine (potent) | Antidepressants • Norfluoxetine (fluoxetine's main metabolite)(weak/moderate)[4][5] • Fluvoxamine (weak/moderate)[6] |
Substrates | Antidepressants • Tricyclics (demethylation) • Fluvoxamine • Trazodone • Duloxetine • Mirtazapine • Agomelatine Antipsychotics • Haloperidol • Thioridazine • Clozapine • olanzapine • Asenapine | Antidepressants • Bupropion | Antidepressants • Fluoxetine Mood stabilizers • Valproic acid Hypnotics • Zolpidem • Zopiclone | Antidepressants • Tricyclics (demethylation) • Sertraline • Citalopram • Escitalopram • Moclobemide Anxiolytics • Diazepam • Clobazam | Antidepressants • Tricyclics (hydroxylation) • Fluoxetine • Fluvoxamine • Paroxetine • Citalopram, • Escitalopram • Venlafaxine • Mirtazapine • Duloxetine • Vortioxetine • Atomoxetine Antipsychotics • Haloperidol • Chlorpromazine • Fuphenazine • Perphenazine • Thioridazine • Zuclopenthixol • Pimozide • Clozapine • Olanzapine • Risperidone • Iloperidone • Aripiprazole • Brexpiprazole | Antidepressants • Tricyclics (demethylation) • Sertraline • Citalopram • Escitalopram • Venlafaxine • Mirtazapine • Trazodone • Reboxetine • Vilazodone Antipsychotics • Haloperidol • Thioridazine • Pimozide • Clozapine • Quetiapine, • Risperidone • Iloperidone • Aripiprazole • Brexpiprazole • Ziprasidone • Lurasidone • Cariprazine Anxiolytics • Alprazolam • Midazolam • Tiazolam Mood stabilizers • Carbamazepine |
Non-psychotropic examples | • Acetaminophen (substrate) • Caffeine (substrate) | - | - | - | • Codeine (inhibitor) • Beta-blockers, dextromethorphan (substrates) | • Clarithromycin (inhibitor) • Atorvastatin (substrate) • Amlodpine (substrate) |
Metabolizer Phenotype | Effect on Drug Metabolism | Possible Outcomes |
---|---|---|
Poor to intermediate | Slow | • Poor drug efficacy • Higher risk for therapeutic failure • Accumulation of prodrug • Patient at increased risk of drug side effects |
Ultrarapid | Fast | • Good drug efficacy/response • Rapid effect |
Metabolizer Phenotype | Effect on Drug Metabolism | Possible Outcomes |
---|---|---|
Poor to intermediate | Slow | • Good drug efficacy • Accumulation of active drug • Patient at increased risk of drug-induced side effects • Patient requires lower dosage |
Ultrarapid | Fast | • Poor drug efficacy • Higher risk for therapeutic failure • Patient requires higher dosage |