Appendix J. Cytochrome P450 (CYP) enzymes

Most drugs are eliminated from the body, at least in part, by being changed chemically to a less lipid-soluble product (i.e., metabolized) and thus more likely to be excreted from the body via the kidney or bile. Drugs may go through two different metabolic processes: phase 1 and phase 2 metabolism.

In phase 1 metabolism, hepatic microsomal enzymes found in the endothelium of liver cells metabolize drugs via hydrolysis and oxidation and reduction reactions. These chemical reactions make the drug more water soluble. In phase 2 metabolism, large water-soluble substances (e.g., glucuronic acid, sulfate) are attached to the drug, forming inactive, or significantly less active, water-soluble metabolites. Phase 2 processes include glucuronidation, sulfation, conjugation, acetylation, and methylation.

Virtually any of the phase 1 and phase 2 enzymes can be inhibited, and some of these enzymes can be induced by drugs. Inhibiting the activity of metabolic enzymes results in increased concentrations of the drug (substrate), whereas inducing metabolic enzymes results in decreased concentrations of the drug (substrate).

The term “cytochrome P450” (CYP enzymes) refers to a family of more than 100 enzymes in the human body that modulate various physiologic functions. First identified in the 1950s, the CYP enzyme system contains two large subgroups: steroidogenic and xenobiotic enzymes. Only the xenobiotic group is involved in the metabolism of drugs. The xenobiotic group includes four major enzyme families: CYP1, CYP2, CYP3, and CYP4. The primary role of these families is the metabolism of drugs. These families are further subdivided into subfamilies designated by a capital letter and given a specific enzyme number (1, 2, 3, etc.) according to the similarity in amino acid sequence it shares with other enzymes (e.g., CYP1A2).

The key CYP450 enzymes include CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 and may be responsible for metabolism of 75% of all drugs, with the CYP3A subfamily responsible for nearly half of this activity.

The CYP enzymes are found in the endoplasmic reticulum of cells in a variety of human tissue but are primarily concentrated in the liver and intestine. CYP enzymes can be both inhibited and induced, leading to increased or decreased serum concentration of the drug (along with its effects).

The following tables of CYP substrates, inhibitors, and inducers provide a perspective on drugs that are affected by, or affect, cytochrome P450 (CYP) enzymes. CYP substrate includes drugs reported to be metabolized, at least in part, by one or more CYP enzymes. CYP inhibitor includes drugs reported to inhibit one or more CYP enzymes. CYP inducer contains drugs reported to induce one or more CYP enzymes.

P450 ENZYMES: SUBSTRATES, INHIBITORS, INDUCERS

CYP1A2 ENZYME

CYP1A2 SUBSTRATES	CYP1A2 INHIBITORS	CPY1A2 INDUCERS
Caffeine	Cimetidine (Tagamet)	Barbiturates
Clozapine (Clozaril)	Ciprofloxacin (Cipro)	Carbamazepine (Tegretol)
Mirtazapine (Remeron)	Fluvoxamine	Rifampin (Rifadin)
Olanzapine (Zyprexa)	Zileuton (Zyflo)	Smoking
Ramelteon (Rozerem)
Ropinirole (Requip)
Tizanidine (Zanaflex)

• CYP1A2 enzyme is increasingly involved in drug interactions.

• More potent inhibitors include cimetidine, ciprofloxacin, and fluvoxamine.

• Smoking is the most important inducer, but rifampin and barbiturates also can increase enzyme activity.

• Example of reaction: Tizanidine plasma concentrations increased more than 30-fold when the inhibitor fluvoxamine was given concurrently.

CYP2C9 ENZYME

CYP2C9 SUBSTRATES	CYP2C9 INHIBITORS	CYP2C9 INDUCERS
Candesartan (Atacand)	Amiodarone (Cordarone)	Barbiturates
Celecoxib (Celebrex)	Clopidogrel (Plavix)	Carbamazepine (Tegretol)
Diclofenac (Voltaren)	Fluconazole (Diflucan)	Rifampin (Rifadin)
Glipizide (Glucotrol)	Metronidazole (Flagyl)	St. John’s wort
Glyburide (DiaBeta)	Sulfamethoxazole
Ibuprofen (Advil, Motrin)	Valproic acid (Depakote)
Irbesartan (Avapro)
Meloxicam (Mobic)
Warfarin (Coumadin)

• More potent inhibitors include amiodarone, metronidazole, and sulfamethoxazole.

• All of the inducers can substantially increase enzyme activity.

• Both warfarin and oral hypoglycemics are of serious concern with regard to drug interactions. Substrates warranting attention include warfarin and oral hypoglycemics.

CYP2C19 ENZYME

CYP2C19 SUBSTRATES	CYP2C19 INHIBITORS	CYP2C19 INDUCERS
Citalopram (Celexa)	Cimetidine (Tagamet)	Barbiturates
Diazepam (Valium)	Clopidogrel (Plavix)	Carbamazepine (Tegretol)
Escitalopram (Lexapro)	Esomeprazole (Nexium)	Rifampin (Rifadin)
Omeprazole (Prilosec)	Fluconazole (Diflucan)	St. John’s wort
Pantoprazole (Protonix)	Fluvoxamine
Sertraline (Zoloft)	Modafinil (Provigil)

• Inhibition by itself does not frequently cause adverse effects compared with other CYP enzymes because many of the substrates do not have serious toxicity.

• Inhibition or induction of the enzyme nonetheless may result in an adverse drug interaction.

• Racial background is important in the likelihood of being deficient in this enzyme (e.g., 3%–5% of Caucasians and 12%–23% of Asians are poor metabolizers of this enzyme).

CYP2D6 ENZYME

CYP2D6 SUBSTRATES	CYP2D6 INHIBITORS	CYP2D6 INDUCERS
Amitriptyline (Elavil)	Amiodarone (Cordarone)	See comment below
Atomoxetine (Strattera)	Bupropion (Wellbutrin)
Duloxetine (Cymbalta)	Fluoxetine (Prozac)
Fluoxetine (Prozac)	Paroxetine (Paxil)
Metoclopramide (Reglan)
Metoprolol (Lopressor)
Paroxetine (Paxil)
Risperidone (Risperdal)
Tamoxifen (Nolvadex)
Tolterodine (Detrol)
Tramadol (Ultram)
Venlafaxine (Effexor)

• Potent inhibitors include fluoxetine and paroxetine.

• Evidence suggests that this enzyme is not very susceptible to enzyme induction.

• Genetics, rather than drug therapy, accounts for most ultra-rapid metabolizers (e.g., Greeks, Portuguese, Saudis, and Ethiopians have high enzyme activity).

CYP3A4 ENZYME

CYP3A4 SUBSTRATES	CYP3A4 INHIBITORS	CYP3A4 INDUCERS
Alfuzosin (Uroxatral)	Amiodarone (Cordarone)	Carbamazepine (Tegretol)
Alprazolam (Xanax)	Clarithromycin (Biaxin)	Efavirenz (Sustiva)
Budesonide (Entocort EC)	Diltiazem (Cardizem)	Phenobarbital
Carbamazepine (Tegretol)	Erythromycin (Ery-Tab)	Rifampin (Rifadin)
Cyclosporine (Neoral)	Fluconazole (Diflucan)	St. John’s wort
Fluticasone (Flovent)	Fluoxetine (Prozac)
Lovastatin (Mevacor)	Itraconazole (Spoiranox)
Repaglinide (Prandin)	Ketoconazole (Nizoral)
Sildenafil (Viagra)	Verapamil (Calan, Isoptin)
Simvastatin (Zocor)
Tadalafil (Cialis)

• This enzyme metabolizes about half of all medications on the market.

• Drug toxicity of CYP3A4 substrates due to inhibition of CYP3A4 is relatively common.

• This enzyme is very sensitive to induction, tending to lower plasma concentrations of substrates, resulting in reduced efficacy of the substrate.

• Most potent inhibitors include clarithromycin, itraconazole, and ketoconazole.

• Rifampin is a potent inducer and may reduce serum concentrations of substrates by as much as 90%.