- Last edited on April 1, 2024
Cytochrome (CYP) P450 Metabolism
Primer
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.
Metabolism
See main article: Introduction to Pharmacology: Metabolism
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:
- Phase I: oxidative reactions, catalyzed via Cytochrome enzymes
- Phase II: glucuronide conjugation, which occurs through UDP-glucuronosyltransferases (UGT).
Substrates, Inhibitors, and Inducers
- Drugs which are metabolized by a CYP enzyme are called substrates.
- Drugs may also inhibit or induce the action of the CYP enzyme (or have no effect on it).
- Drugs that inhibit a CYP enzyme, decreases the activity of that CYP enzyme. This increases the plasma concentrations of the drug, or decreases clearance of its substrates.
- Drugs that induce a CYP enzyme, increases the activity of that CYP enzyme. This decreases the plasma concentration of the affected drug, or increases clearance of its substrates.
Naming System
CYP enzymes are classified into families and subfamilies according to similarities in their amino acid sequence. Each enzyme always starts with[1]:
- The three letters, CYP, which stands for cytochrome P450
- Followed by a number (1, 2, or 3) indicating the family (e.g. - 1)
- A letter indicating the subfamily (e.g. - A)
- And another number denoting the specific isoform (e.g. - 2)
- The final enzyme name would be something like CYP1A2
Polymorphisms
- There is a large amount of environmental and genetic polymorphisms of the CYP enzymes, meaning each individual has a different ability to metabolize drugs. Pharmacogenetic testing is increasingly being used to identify these differences, but there few clinical applications at this time.
- For example, individuals of Asian and Hispanic descent have less CYP 1A2 activity, and therefore need lower doses of antipsychotics to achieve similar treatment response.[2]
CYP Table
See also: Flockhart Table for a detailed drug interactions mediated by cytochrome P450 enzymes.
CYP Table
| 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) |
Examples
Poor and Fast Metabolizers
- Genetic polymorphisms exist for many of the CYP450 enzymes – this means there are groups of individuals whose ability to metabolize a drug can range from extremely poor to extremely fast.
- The most common polymorphisms are found in CYP2D6, CYP2C19, CYP2C9
- Depending on if a drug's mechanism of action, these polymorphisms can be different effects on patient response and side effects (see table below) – just because someone is a poor metabolizer does not mean they won't respond to a drug (in fact it could mean a better response)!
- Or vice versa, if an active drug (e.g. - omeprazole) is metabolized into the inactive form (5-hydroxyomeprazole)
Prodrug Outcomes
Adapted from: Belle, Donna J. et al. Genetic factors in drug metabolism. American family physician 77.11 (2008): 1553-1560.| 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 |
Active → Inactive Drug Outcomes
Adapted from: Belle, Donna J. et al. Genetic factors in drug metabolism. American family physician 77.11 (2008): 1553-1560.| 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 |
Race and Ethnicity
CYP2D6 and Tramadol
See main article: Tramadol
- The story of tramadol can be a helpful way of seeing why understanding CYP450 metabolism is so important!
CYP2D6 and SSRIs
- SSRIs such as fluoxetine, paroxetine, sertraline, and citalopram are inhibitors of CYP2D6.
- Co-administration of SSRIs with medications that are substrates of CYP2D6 will increase the serum concentrations of those medications, including beta-blockers such as labetalol, metoprolol, propranolol, and timolol.
- Type 1C antiarrhythmics such as encainide, flecainide, propafenone, and mexiletine are also CYP2D6 substrates.
CYP1A2, Smoking, and Antipsychotics
See also: Olanzapine (Zyprexa) and Clozapine (Clozaril)
- Polycyclic aromatic hydrocarbons (PAHs) found in cigarette smoke can induce cytochrome P450 (CYP) isoenzymes, specifically CYP1A1, CYP1A2, and CYP2E1.
- Both olanzapine and clozapine are primarily metabolized by CYP1A2 (close to 70%).
- Thus smoking can induce faster metabolism, while abruptly stopping smoking can inadvertently increase antipsychotic levels.
- It is generally recommended that smoker patients on clozapine or olanzapine who decide to quit smoking have a 40% reduction in their dose by 10% per day, up to 40%.[9]
- Nicotine replacement products (patches, lozenges, nasal spray, inhalers, and gum) and electronic cigarettes on the other hand, do not induce CYP1A2.
Resources
Articles
References
1)
Nelson DR. The cytochrome p450 homepage. Hum Genomics 2009;4:59-65.Nelson DR. The cytochrome p450 homepage. Hum Genomics 2009;4:59-65.
2)
Subramaniam, M., Ng, C., Chong, S. A., Mahendran, R., Lambert, T., Pek, E., & Huak, C. Y. (2007). Metabolic differences between Asian and Caucasian patients on clozapine treatment. Human Psychopharmacology: Clinical and Experimental, 22(4), 217-222.
3)
Lakehal, F., Wurden, C. J., Kalhorn, T. F., & Levy, R. H. (2002). Carbamazepine and oxcarbazepine decrease phenytoin metabolism through inhibition of CYP2C19. Epilepsy research, 52(2), 79-83.
4)
Hemeryck, A., & Belpaire, F. M. (2002). Selective serotonin reuptake inhibitors and cytochrome P-450 mediated drug-drug interactions: an update. Current drug metabolism, 3(1), 13–37.
5)
Leucker, T. M., Singh, S., & Moffett, B. K. (2013). Fluoxetine inhibition of CYP3A4 potentiating adrenal suppression and peptic ulcer disease from intra-articular triamcinolone injections. Pain Medicine, 14(6), 952-953.
6)
van Harten, J. (1995). Overview of the pharmacokinetics of fluvoxamine. Clinical pharmacokinetics, 29(Suppl 1), 1-9.
7)
Bernard, S., Neville, K. A., Nguyen, A. T., & Flockhart, D. A. (2006). Interethnic differences in genetic polymorphisms of CYP2D6 in the US population: clinical implications. The oncologist, 11(2), 126-135.
8)
De Leon, J., Schoretsanitis, G., Smith, R. L., Molden, E., Solismaa, A., Seppälä, N., ... & Müller, D. J. (2022). An international adult guideline for making clozapine titration safer by using six ancestry-based personalized dosing titrations, CRP, and clozapine levels. Pharmacopsychiatry, 55(02), 73-86.