Cytochrome (CYP) P450 Metabolism

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:

  1. Phase I: oxidative reactions, catalyzed via Cytochrome enzymes
  2. Phase II: glucuronide conjugation, which occurs through UDP-glucuronosyltransferases (UGT).
  • 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.

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

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]

See also: Flockhart Table for a detailed list.

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 • 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 (moderate)
Duloxetine (moderate)
Bupropion (moderate)

Antipsychotics
• Perphenazine (potent)
Antidepressants
• Fluoxetine (moderate)
Fluvoxamine (moderate)
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 (substrates)
• Clarithromycin (inhibitor)
• Atorvastatin (substrate)
• Amlodpine (substrate)
  • Poor 2D6 metabolism is present in up to 10% of Caucasians, up to 8% of Blacks, 2-7% of Hispanics, 2-5% of South Asians, 1-2% of Saudi Arabians, and 0-1% of East/Southeast Asians.[3]

The story of tramadol can be a helpful way of seeing why understanding CYP450 metabolism is so important!

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. As a potent CYP2D6 inhibitor, fluoxetine may produce hypoglycemia in patients with diabetes who use insulin.

The polycyclic aromatic hydrocarbons from 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 smoking patients who are on clozapine or olanzapine and decide to quit smoking have a 40% reduction in their dose by 10% per day, up to 40%. Nicotine replacement products (patches, lozenges, nasal spray, inhalers, and gum) and electronic cigarettes on the other hand, do not induce CYP1A2.