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- Please note
- The information presented here is NOT A COMPLETE LIST of CYP2C19 inducers, inhibitors, and substrates
- Not all drug interactions are clinically significant. Potential drug interactions should be researched, and medication changes should only be made after consulting a health professional.
- ACRONYMS AND DEFINITIONS
- CYP - Cytochrome P450
- Substrate - a drug that is metabolized by a certain enzyme is a substrate of that enzyme
- CYTOCHROME P450
- Overview
- Cytochrome P450 (often abbreviated "CYP") is a class of enzymes that is involved in the metabolism of many medications
- Cytochrome P450 enzymes are located primarily in the liver
- Cytochrome P450 enzymes are subdivided into classes (e.g. 2D6, 3A4, 2C8, etc.) based on their structure
- Drug metabolism
- Drugs may be metabolized by one subclass of CYP enzyme (ex. 3A only), or they may be metabolized by a number of CYP enzymes (ex. 2C8, 3A4, and 2C19)
- In some cases, one CYP enzyme may be responsible for the majority of the drug's metabolism while other CYP enzymes contribute a nonsignificant amount of metabolism
- Some drugs undergo no CYP metabolism
- CYP drug interactions
- Inducers and Inhibitors
- Inducers - CYP inducers increase the activity of CYP enzymes. This may increase the metabolism of other drugs that are substrates of the enzyme reducing their exposure.
- Inhibitors - CYP inhibitors reduce the activity of CYP enzymes. This may decrease the metabolism of other drugs that are substrates of the enzyme increasing their exposure.
- Certain chemicals and foods (ex. tobacco smoke and grapefruit juice) may also act as CYP inducers and inhibitors
- Drugs may be metabolized by a CYP enzyme while also inhibiting or inducing the enzyme at the same time
- Inducers and inhibitors can be subdivided into strong, moderate, or weak based on how much of an effect they have on the enzyme
- Competitive inhibition
- If two drugs are metabolized by the same CYP enzyme, they may "compete" for the enzyme and this can alter the metabolism of one or both of the drugs
- Compounded interactions
- When a person is taking three or more drugs, the potential for compounded interactions exists
- Compounding can also occur between CYP enzymes and cell transport systems (ex. p-glycoprotein, OAT, etc.)
- Example:
- Drug A is metabolized by CYP2D6 and CYP2C9
- Drug B inhibits CYP2D6. Drug C inhibits CYP2C9
- When Drug A is taken with Drug B, its elimination is partially decreased, but it is not significant
- When Drug A is taken with Drug B and Drug C, its elimination is decreased substantially and the interaction becomes significant
- Genetic factors
- Different genes code for each CYP enzyme
- Since individuals vary in their genetic makeup, their CYP genes may also vary
- Some people have genes that produce CYP enzymes that are less effective
- These people are often referred to as "poor metabolizers"
- Gene variations in CYP enzymes can affect how an individual metabolizes a drug
- CYP2C19 POOR METABOLIZERS
- Overview
- Different forms of a gene are called alleles. Individuals and populations can vary in the alleles they carry for a gene.
- Variations in alleles that code for CYP enzymes can affect the performance of these enzymes. Some alleles may decrease the activity of the enzyme (loss-of-function alleles), while other alleles may increase the activity.
- Studies have shown that the prevalence of CYP2C19 alleles varies by ethnicity, and these variations affect the metabolic activity of the CYP2C19 enzyme
- One loss-of-function allele leads to a 47% reduction in CYP2C19 activity, and two loss-of-function alleles leads to a 65% reduction
- People with one loss-of-function allele are considered "intermediate metabolizers," and people with two loss-of-function alleles are considered "poor metabolizers" [12]
- CYP2C19 metabolizer-status is particularly important because the widely prescribed antiplatelet agent clopidogrel (Plavix®) must be metabolized by CYP2C19 to become active (see clopidogrel and CYP2C19 poor metabolizers)
- Prevalence of at least one loss-of-function allele by ethnicity (intermediate metabolizers)
- Asians 51 - 55%
- African-Americans 33 - 40%
- Caucasians 24 - 30%
- Mexican-Americans 18% [12]
- Prevalence of two loss-of-function alleles by ethnicity (poor metabolizers)
- Chinese 14%
- African-Americans 4%
- Caucasians 2% [13]
- IMPORTANT POINTS ABOUT DRUG INTERACTIONS
- Drug interactions are challenging
- Information on drug interactions can be difficult to assimilate
- Certain drug interactions and metabolic pathways are well-documented while many are not
- Factors that can make drug interactions challenging
- New drugs
- When a new drug is being developed, the FDA requires that it be tested for drug interactions with a small number of medications that are known to have significant interactions
- Obviously, there is no way to test a medication in every possible drug combination that may occur. This means most drugs come to market with incomplete drug interaction profiles.
- After a medication is prescribed to a large number of people, other drug interactions are inevitably discovered
- Research
- Much of the research involving drug metabolism and drug interactions occurs in vitro meaning in a lab, or outside of the human body
- Animal models and cell cultures are often used to test drugs for metabolic pathways and interactions
- Findings from in vitro experiments do not always translate into what actually happens in the human body (in vivo)
- Evolving information
- Drug metabolism is an evolving field of medicine and pharmacology
- Researchers are just beginning to understand all the different systems that are involved in how the body metabolizes and eliminates drugs
- Cell transport systems (ex. p-glycoprotein, OAT, etc.) are a relatively new area of pharmacology and information about how these systems affect drug elimination is evolving
- Important points
- Not all drug interactions are known or can be predicted
- Good information on possible drug interactions may not be available
- Not all drug interactions are significant
- Always consult your physician or pharmacist before changing your medication if you are concerned about a possible drug interaction
- CYP2C19 INDUCERS
- CYP2C19 moderate inducers
- Enzalutamide (Xtandi®) [4]
- Rifampin [1]
- CYP2C19 inducers (class not well-defined)
- Tocilizumab (Actemra®) - indirect induction through inflammation suppression [6]
- Tumor Necrosis Factor inhibitors - indirect induction through inflammation suppression - (adalimumab, Humira®, certolizumab, Cimzia®, etanercept, Enbrel®, golimumab, Simponi®, infliximab, Remicade®) [6]
- St. John's Wort (Hypericum perforatum) [10,11]
- CYP2C19 INHIBITORS
- CYP2C19 strong inhibitors
- Amitriptyline (Elavil®) [9]
- Clomipramine (Anafranil®) [9]
- Fluconazole (Diflucan®) [1]
- Fluvoxamine (Luvox®) [1]
- Imipramine (Tofranil®) [9]
- Ticlopidine (Ticlid®) [1]
- CYP2C19 moderate inhibitors
- Esomeprazole (Nexium®) [1]
- Fluoxetine (Prozac®) [1]
- Moclobemide [1]
- Omeprazole (Prilosec®) [1]
- Voriconazole (Vfend®) [1]
- CYP2C19 weak inhibitors
- Allicin (garlic derivative) [1]
- Armodafinil (Nuvigil®) [1]
- Carbamazepine (Tegretol®) [1]
- Cimetidine (Tagamet®) [1]
- Desipramine (Norpramin®) [9]
- Etravirine (Intelence®) [1]
- Ethinyl estradiol [1]
- Felbamate [1]
- Fenofibrate (Tricor®, etc) [4]
- Fenofibric acid (Trilipix®) [4]
- Human growth hormone (HGH) [1]
- Ketoconazole (Nizoral®) [1]
- Nortriptyline (Pamelor®) [9]
- Oral contraceptives [1]
- Topiramate (Topamax®) [4]
- CYP2C19 inhibitors (class not well-defined)
- Lansoprazole (Prevacid®) [7]
- Nicardipine (Cardene®) [4]
- Oxcarbazepine (Trileptal®) [4]
- Telmisartan (Micardis®) [4]
- Vilazodone (Viibryd®) - in vitro studies only [4]
- CYP2C19 SUBSTRATES
- CYP2C19 sensitive substrates
- NOTE: These drugs are known to be significantly affected by CYP2C19 inhibitors/inducers
- Carisoprodol (Soma®) [4,7]
- Citalopram (Celexa®) [4]
- Clobazam (Onfi®) [4]
- Clopidogrel (Plavix®) [4]
- Diazepam (Valium®) [4,7]
- Flibanserin (Addyi®) - minor substrate [4]
- Lansoprazole (Prevacid®) [1]
- Omeprazole (Prilosec®) [1]
- Phenytoin (Dilantin®) [1]
- Tofacitinib (Xeljanz®) [4]
- CYP2C19 substrates
- Amitriptyline (Elavil®) [7]
- Apixaban (Eliquis®) [4]
- Arformoterol (Brovana®) [4]
- Chloramphenicol [2]
- Clomipramine (Anafranil®) [7]
- Cyclophosphamide [2]
- Doxazosin (Cardura®, Cardura XL®) [4, Cardura XL® PI]
- Fluoxetine (Prozac®) [7]
- Formoterol (Foradil®) [4]
- Imipramine (Tofranil®) [7]
- Indomethacin (Indocin®) [2]
- Methadone [4]
- Nelfinavir (Viracept®) [7]
- Nilutamide (Nilandron®) [2]
- Nortriptyline (Pamelor®) [7]
- Ospemifene (Osphena®) [4]
- Pantoprazole (Protonix®) [1]
- Prasugrel (Effient®) [4]
- Praziquantel (Biltricide®) [3]
- Primidone (Mysoline®) [2]
- Progesterone [2]
- Proguanil (Malarone®) [7]
- Propranolol (Inderal®) [4]
- Rabeprazole (Aciphex®) [7]
- Sertraline (Zoloft®) [7]
- Suvorexant (Belsomra®) (minor substrate) [4]
- Teniposide [2]
- Terbinafine (Lamisil®) [4]
- Timolol (Timoptic®, Blocadren®) (minor substrate) [14]
- Voriconazole (Vfend®) [4]
- Warfarin (Coumadin®) [2]
- BIBLIOGRAPHY
- 1 - FDA drug development and drug interactions - CLICK HERE
- 2 - Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana University School of Medicine (2007). http://medicine.iupui.edu/clinpharm/ddis/table.aspx. Accessed [2011].
- 3 - SuperCYP
- 4 - Manufacturer's Package Insert
- 5 - PubMed ID 11956508
- 6 - PubMed ID 11602509
- 7 - PubMed ID 12222994
- 8 - PubMed ID 21060077
- 9 - PubMed ID 17471183
- 10 - Carisoprodol PI
- 11 - PubMed ID 22606944
- 12 - PubMed ID 21060077
- 13 - Clopidogrel PI
- 14 - PMID 17461033 Timolol metabolism