CYTOCHROME P450 1A2
Please note
- The information presented here is NOT A COMPLETE LIST of CYP1A2 inducers, inhibitors, and substrates
- An easy way to quickly search the drug lists is with your browser's Search/Find (Ctrl+F) tool
- 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.
- CYP - Cytochrome P450
- FDA - U.S. Food and Drug Administration
- Substrate - a drug that is metabolized by a certain enzyme is a substrate of that enzyme
- CYTOCHROME P450
- 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 (ex. 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
- Some drugs affect the action of CYP enzymes:
- Inducers - increase the
activity of CYP enzymes
- Inhibitors - block the action
of CYP enzymes
- When CYP inducers or inhibitors are taken with other medications that
are metabolized by the same enzyme, they can alter the metabolism of that
medication
- 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 and also inhibit or induce 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
- 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
- Compounding can also occur between CYP enzymes and cell transport
systems (ex. p-glycoprotein, OAT, etc.)
- 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
- 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 include the following:
- 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, or 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
- INTERACTION
- If Drug A is metabolized by CYP1A2, and it is taken with Drug B, a
CYP1A2 inducer, then blood levels of Drug A may be decreased
- Example:
- Drug A is metabolized by CYP1A2. Drug B is a CYP1A2 inducer.
- Drug A by itself = normal blood levels
- Drug A + Drug B = decreased levels of Drug A because Drug B has
increased CYP1A2 activity
CYP1A2 moderate inducers
- Montelukast (Singulair®) [1]
- Phenytoin (Dilantin®) [1]
- Smoking tobacco induces CYP1A2 [1]
CYP1A2 weak inducers
- Omeprazole (Prilosec®) [1]
- Phenobarbital [1]
CYP1A2 inducers (class uncertain)
- Albendazole (Albenza®) [7]
- Broccoli [2,8]
- Brussel sprouts [2,8]
- Carbamazepine (Tegretol®) [7]
- Char-grilled meat [2,8]
- Tocilizumab (Actemra®) - indirect induction through inflammation suppression
[7]
- Tumor Necrosis Factor inhibitors - indirect induction through inflammation
suppression - (adalimumab, Humira®, certolizumab, Cimzia®, etanercept, Enbrel®,
golimumab, Simponi®, infliximab, Remicade®) [7]
- INTERACTION
- If a Drug A is metabolized by CYP1A2, and it is taken with Drug B, a
CYP1A2 inhibitor, then blood levels of Drug A may increase
- Example:
- Drug A is metabolized by CYP1A2. Drug B is a CYP1A2 inhibitor.
- Drug A by itself = normal blood levels
- Drug A + Drug B = increased blood levels of Drug A because Drug B has
inhibited CYP1A2
CYP1A2 strong inhibitors
- Ciprofloxacin (Cipro®) [1]
- Fluvoxamine (Luvox®) [1]
CYP1A2 moderate inhibitors
- Imipramine (Tofranil®) [9]
- Methoxsalen (Psoralen®) [1]
- Mexiletine [1]
- Oral contraceptives [1]
- Phenylpropanolamine [1]
- Thiabendazole [1]
- Zileuton (Zyflo®) [1]
CYP1A2 weak inhibitors
- Acyclovir (Zovirax®) [1]
- Allopurinol (Zyloprim®) [1]
- Caffeine [1]
- Cimetidine (Tagamet®) [1]
- Daidzein (supplement) [1]
- Disulfiram (Antabuse®) [1]
- Echinacea [1]
- Famotidine (Pepcid®) [1]
- Glecaprevir (Mavyret™) [7]
- Norfloxacin (Noroxin®) [1]
- Pibrentasvir (Mavyret™) [7]
- Propafenone (Rythmol®) [1]
- Propranolol (Inderal® [1]
- Simeprevir (Olysio®) [7]
- Terbinafine (Lamisil®) [1]
- Ticlopidine (Ticlid®) [1]
- Verapamil (Calan®, Covera-HS®, Verelan®, etc) [1]
CYP1A2 inhibitors (class uncertain)
- Amiodarone (Cordarone®) [7]
- Amitriptyline (Elavil®) [9]
- Gemfibrozil (Lopid®) [7]
- Isoniazid [8]
- Peginterferon alfa-2a (Pegasys®) [7]
- Peginterferon alfa-2b (PegIntron®) [7]
- INTERACTION
- CYP1A2 substrates may be affected by CYP1A2 inducers and inhibitors (see
above)
- If two CYP1A2 substrates are taken together, they may compete for the
enzyme and the metabolism of one or both of the drugs may be affected
- Sensitive substrates are drugs that are known to be significantly
affected by CYP1A2 inhibitors and/or inducers
- Example:
- Drug A is metabolized by CYP1A2. Drug B is metabolized by CYP1A2.
- When Drug A is taken with Drug B they may compete for the CYP1A2
enzyme
- This competition may affect blood levels of either one or both of the
drugs
CYP1A2 sensitive substrates
- NOTE: These drugs are known to be
significantly affected by CYP1A2 inhibitors/inducers
- Alosetron (Lotronex®) [1]
- Caffeine [1]
- Clozapine (Clozaril®) [7]
- Duloxetine (Cymbalta®) [1]
- Melatonin [1]
- Olanzapine (Zyprexa®) [7]
- Ramelteon (Rozerem®) [1, 7]
- Roflumilast (Daliresp®) [7]
- Ropinirole (Requip®) [7, 8]
- Theophylline (Theo-Dur®, Theo-24®) - has narrow therapeutic range [1]
- Thioridazine (Mellaril®) [8]
- Tizanidine (Zanaflex®) - has narrow therapeutic range [1,7]
CYP1A2 substrates
- Alcohol (ethanol) [4]
- Amitriptyline (Elavil®) [8]
- Apixaban (Eliquis®) [7]
- Asenapine (Saphris®) [7]
- Clomipramine (Anafranil®) [8]
- Clopidogrel (Plavix®) [7]
- Cyclobenzaprine (Flexeril®) [8]
- Dacarbazine [8]
- Estradiol (Estrace®) [8]
- Ethanol (beverage alcohol) [4]
- Febuxostat (Uloric®) [7]
- Flutamide [8]
- Fluvoxamine (Luvox®) [8]
- Frovatriptan (Frova®) [7]
- Haloperidol (Haldol®) [8]
- Imipramine (Tofranil®) [8]
- Leflunomide (Arava®) [8]
- Metaxalone (Skelaxin®) [7]
- Mexiletine [7]
- Mirtazapine (Remeron®) [7]
- Nabumetone (Relafen®) [8]
- Naproxen (Aleve®) [8]
- Ondansetron (Zofran®) [8]
- Pentoxifylline (Trental®) [8]
- Praziquantel (Biltricide®) [3]
- Propafenone (Rythmol®) [7, 8]
- Propranolol (Inderal®) [7]
- Terbinafine (Lamisil®) [7]
- Triamterene [5]
- Verapamil (Calan®) [8]
- Voxilaprevir (Vosevi™) [7]
- Warfarin (Coumadin®) [8]
- Zileutin (Zyflo®) (in vitro data) [7]
- Zolmitriptan (Zomig®) [8]
- Zolpidem (Ambien®) [3]
- What is PMID?
- PI = Manufacturer's Package Insert
- # PMID
- 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 -PMID 9884161
- 5 - PMID 16035375
- 6 - PMID 11602509
- 7 - Manufacturer's package insert (for referenced drug)
- 8 - PMID 19961320
- 9 - PMID 17471183
