Quick Summary
- Inducers Cause: Increase in CYP enzymes/metabolism =’s LESS drug action (due to more enzymes available to break the drug down)
- Inhibitors Cause: Decrease in CYP enzymes/metabolism=’s MORE drug action (due to fewer enzymes available to break the drug down)
The CYP450 enzymes are essential for the production of numerous agents including cholesterol and steroids. Additionally, these enzymes are necessary for the detoxification of foreign chemicals and the metabolism of drugs. CYP450 enzymes are so named because they are bound to membranes within a cell (cyto) and contain a heme pigment (chrome and P) that absorbs light at a wavelength of 450 nm when exposed to carbon monoxide.
There are more than 50 CYP450 enzymes, but the CYP1A2, CYP2C19, CYP2D6, CYP1A2, CYP3A4, and CYP3A5 enzymes are responsible for metabolizing 45% of drug metabolism. The CYP2D6 (20–30%), the CYP2C9 (10%), and the CYP2E1 and CYP1A2 (5%) complete this enzyme system.
Some Enzymes and Selected Substrates
- 1A2: Antipsychotics, Benzodiazepines, Fluvoxamine, Theophylline, Warfarin
- 2C: Amitriptyline, Clomipramine, Omeprazole, Phenytoin, Warfarin
- 2D6: B-blockers, Codeine, Risperidone, Trazodone, Venlafaxine Haloperidol
- 3A4: Antihistamines, Calcium channel blockers, Carbamazepine, Cisapride, Corticosteroids, Cyclosporine, Fentanyl, Protease Inhibitors, Statins, Triazolobenzodiazepine
Drugs that cause CYP450 drug interactions are referred to as either inhibitors or inducers.
An inducing agent can increase the rate of another drug’s metabolism by as much as two- to threefold that develops over a period of a week. When an inducing agent is prescribed with another medication, the dosage of the other medication may need to be adjusted since the rate of metabolism is increased and the effect of the medication reduced. This can lead to a therapeutic failure of the medication.
Conversely, if a medication is taken with an agent that inhibits its metabolism, then the drug level can rise and possibly result in a harmful or adverse effect. Information regarding a drug’s CYP450 metabolism and its potential for inhibition or induction can be found on the drug label and accessed through the U.S. Food and Drug Administration (FDA) or manufacturer’s websites.
-The Importance of Multi-P450 Inhibition by Pub Med
When we assess our patients and provide management modalities, these are implemented within a framework of the patient’s heritage, race, and culture. This is also true in pharmacology as well (i.e., “pharmacogenetics”). This concept is important to examine since we know that there exists genetic variability, which may influence a patient’s response to commonly prescribed drug classes.
This genetic variability can be defined as polymorphism. Seven percent of Caucasians and 2–7% of African Americans are poor metabolizers of drugs dependent on CYP2D6, which metabolizes many beta-blockers, antidepressants, and opioids. This is because the drug’s metabolism via CYP450 enzymes exhibits genetic variability.
For example, several antidepressants (paroxetine [Paxil] and fluoxetine [Prozac]) are inhibitors of metabolism when given with drugs metabolized through the CYP2D6 enzyme, such as haloperidol (Haldol), metoprolol (Lopressor), and hydrocodone. Thus, the therapeutic response can be accentuated. Medications that inhibit the CYP3A4 enzyme, such as amiodarone and antifungals, can affect the therapeutic response of fentanyl, alprazolam (Xanax), and numerous statins; as a result, the effect of these drugs can be enhanced leading to potentially toxic levels.
At times, these CYP450 inducers and inhibitors are commonly ingested items such as grapefruit juice and tobacco. In the case of grapefruit juice, there are numerous medications known to interact with grapefruit juice including statins, antiarrhythmic agents, immunosuppressive agents, and calcium channel blockers.
Furthermore, the inhibition of the enzyme system seems to be dose-dependent; thus, the more a patient drinks, the more the inhibition that occurs. Additionally, the effects can last for several days if grapefruit juice is consumed on a regular basis. Luckily, the effect of this is not seen with other citrus juices.
Medications Affected by Grapefruit
Sedatives, Hypnotics, and Anxiolytics
- buspirone (Buspar)
- triazolam (Halcion)
- midazolam (Versed)
- diazepam (Valium)
- zaleplon (Sonata)
- alprazolam (Xanax)
Other Psychotropics
- carbamazepine (Tegretol)
- trazodone (Desyrel)
- quetiapine (Seroquel)
- fluvoxamine (Luvox)
- nefazodone (Serzone)
Hopefully, this brief review has opened the door to your inquisitive nature on how the liver’s enzyme system is affected by numerous medications and why some patients experience clinically significant unanticipated adverse reactions or therapeutic failures.
And more…Caution Patients about Common Food–PSY Drug Interactions
