Knowing whether drugs inhibit or induce cytochrome enzymes affecting bioavailability of coadministered drugs and heeding that knowledge with prescription preferences or dosage adjustments is qualitatively correct practice. More complex and less well-documented are risk-benefit considerations about when and by how much to do so. That the latter depend upon the former is rationale enough to justify commiting to memory (hippocampal or bedside-accessible, digital) lists of substrates, inhibitors, and inducers of cytochrome P450-dependent drug-metabolizing enzyme substrates, inhibitors, and inducers.
In the following lists, “substrates” denotes not only pharmaceutical-grade prescription drugs, but also pharmacologically active alkaloids in plant and animal extracts; natural or synthetic nutritional supplements, seasonings or preservatives; and foodstuffs in which pharmacologically active substances inhere or are formed by methods of manufacture or preparation for consumption (such as charbroiling). By whichever provenience they achieve availability for purchase, once ingested or applied, their “active principles” or preliminary conversion products bind specifically to active sites of a cytochrome P450 isoenzyme before undergoing Phase I metabolism (the first step of clearance, comprising oxidation, epoxidation, hydroxylation, N- and O-dealkylations, dehydrogenation, and aromatization), or (by the same processes) conversion of inactive pro-drug to active metabolite. “Inhibitors” reduce enzyme activity (defined as rate and extent of conversion of substrate to metabolites) and increase bioavailability of substrates. “Inducers” moderate the expression of genes that code for synthesis of (and therefore increase the activities of) metabolic enzymes, enzymes of conjugation, and/or proteins that mediate membrane transport that operate in drug clearance, and thereby reduce bioavailability of therapeutically active substrates and of therapeutically inactive pro-drugs (while increasing bioavailability of therapeutically inactive metabolites and of therapeutically active metabolites of inactive pro-drugs). The principal potential consequence of a pharmacokinetic drug-drug or drug-food interaction is change in the bioavailability of a drug or substance and the biochemical or clinically apparent activity with which it correlates.
Drugs or substances whose bioavailabilities may be affected by inhibitors or inducers of the principal Cytochrome P450 and other metabolic enzymes in humans:
Carboxylesterase 1
Substrates of carboxylesterase 1
Methylphenidate
Inhibitors of carboxylesterase 1
bile acids
diltiazem
fish oil (with eicosapentanoic acid)
CYP1A2
Substrates of CYP1A2
(Inhibitors of CYP1A2 increase the bioavailabilities of the following substrates; inducers of CYP1A2 reduce them.)
Amitriptyline
Caffeine
Chlordiazepoxide
Chlorpromazine
Clomipramine
Clozapine
Cyclobenzaprine
Duloxetine
Estradiol
Fluphenazine
Fluvoxamine
Haloperidol
Imipramine (the N-demethylation step)
Melatonin
Mexiletine
Mirtazapine
Nabumentone
Naproxen
Olanzapine
Ondansetron
Perphenazine
Phenacetin
Propafenone
Propranolol
Riluzole
Ropivacaine
Tacrine
Tamoxifen
Theophylline
Thioridazine
Thiothixene
Tizanidine
Triamterene
Trifluoperazine
Verapamil
R-warfarin
Zileuton
Zolmitriptan
Zolpidem
Inhibitors of CYP1A2
(CYP1A2 inhibitors increase bioavailabilities of CYP1A2 substrates.)
Acyclovir
Allopurinol
Amiodarone
Caffeine
Cannabis constituents
Cimetidine (strong)
Ciprofloxacin (strong)
Diltiazem
Disulfiram
Efavirenz
Estradiol
Famotidine
Fluoroquinolones
Fluvoxamine (strong)
Furafylline
Interferon
Methoxsalen
Mexiletine
Mibefradil
Norfloxacin
Ofloxacin
Phenylpropanolamine
Propafenone
Terbinafine
Thiabendazole
Ticlopidine
Verapamil
Zileuton
Inducers of CYP1A2
(Inducers of CYP1A2 reduce bioavailabilities of CYP1A2 substrates.)
Broccoli
Brussels sprouts
Cannabis (smoked)
Carbamazepine
Cauliflower
Charbroiled meats or vegetables (via combustion-generated polycyclic aromatic hydrocarbons)
Griseofulvin
Insulin
Lansoprazole
Marijuana (smoked)
Methylcholanthrene
Modafinil
Moricizine
Nafcillin
Naphthoflavone (beta)
Omeprazole
Phenobarbital
Phenytoin
Rifampin
Ritonavir
Tobacco (smoked)
CYP2B6
Substrates of CYP2B6
Artemisinin
Bupropion
Cyclophosphamide
Efavirenz
Ifosphamide
Ketamine
Meperidine
Methadone
Nevirapine
Propofol
Selegiline
Inhibitors of CYP2B6
(Inhibitors increase the bioavailabilities of CYP2B6 substrates.)
Clopidogrel
Prasugrel
Thiotepa
Ticlopidine
Voriconazole
Citalopram
Escitalopram
Fluoxetine
Fluvoxamine
Sertraline
Inducers of CYP2B6
(Inducers reduce the bioavailabilities of CYP2B6 substrates.)
Artemisinin
Carbamazepine
Efavirenz
Nevirapine
Phenobarbital
Phenytoin
Rifampin
CYP2C9
Substrates of CYP2C9
Amitriptyline
Fluoxetine
Fluvastatin
Fluvoxamine
Irbesartan
Losartan (prodrug converted to active metabolite)
Nonsteroidal anti-inflammatory agents
Oral hypoglycemic agents
Phenytoin
Sulfonylureas
S-warfarin
Tetrahydrocannabinol
Tolbutamide
Torsemide
Valproic acid
Inhibitors of CYP2C9
(Inhibitors increase the bioavailabilities of CYP2C9 substrates.)
Amiodarone
cotrimoxazole
Flavones and flavonoids
Fluconazole
Fluoxetine
Fluvastatin
Fluvoxamine
Lovastatin
Metronidazole
Miconazole
Oxandrolone
Paroxetine
Phencyclidine
Sertraline
Sulfaphenazole
Sulfapyrazone
Valproic acid
Voriconazole
Zafirlukast
Gingko biloba
Inducers of CYP2C9
(Inducers reduce the bioavailabilities of CYP2C9 substrates.)
Aprepitant
Bosentan
Carbamazepine
Nevirapine
Phenobarbital
Rifampin
Secobarbital
St johns wort
CYP2C19
Substrates of CYP2C19
Esomeprazole
Fluoxetine
Lansoprazole
Omeprazole
Pantoprazole
Inhibitors of CYP2C19
(Inhibitors increase the bioavailabilities of CYP2C19 substrates.)
Allicin (constituent of garlic)
Armodafinil
Carbamazepine
Chloramphenicol
Cimetidine
Esomeprazole
Etravirine
estradiol
Fluconazole
Fluoxetine
Fluvoxamine
Human growth hormone (fhGH)
Ketoconazole
Lansoprazole
Moclobemide
Modafinil
Omeprazole
Oxcarbazepine
Pantoprazole
Ticlopidine
Topiramate
Voriconazole
Inducers of CYP2C19
(Inducers reduce the bioavailabilities of CYP2C19 substrates.)
artemisinin
carbamazepine
efavirenz
norethindrone
prednisone
rifampin
ritonavir
St Johns wort
CYP2D6
Substrates of CYP2D6
Amitriptyline
Clomipramine
Desipramine
Desvenlafaxine
Fluoxetine
Imipramine
Nortriptyline
Paroxetine
Venlafaxine
Chlorpheniramine
Diphenhydramine
Aripiprazole
Chlorpromazine
Haloperidol
Perphenazine
Risperidone and 9-hydroxyrisperidone
Thioridazine
Amphetamine
Atomoxetine
Clonidine
Alprenolol
Atenolol
Bufuralol
S-metoprolol
Nebivolol
Propafenone
Propranolol
Timolol
Carvedilol
Debrisoquine
Dexfenfluramine
Dextromethorphan
Donepezil
Encainide
Lidocaine
Metoclopramide
Mexiletine
Minaprine
Ondansetron
Perhexiline
Phenacetin
Phenformin
promethazine
Tamoxifen
Tramadol (converted to active metabolite)
Codeine
Oxycodone
CYP2D6 Inhibitors
(Inhibitors increase the bioavailabilities of CYP2D6 substrates.)
Most potent
Bupropion
Cinacalcet
Fluoxetine
Paroxetine
Quinidine
Next most potent
Duloxetine
Sertraline
Terbinafine
Least potent of potent inhibitors
Amiodarone
cimetidine
Cannabis constituents
Celecoxib
Chlorpheniramine
Chlorpromazine
Citalopram
Clemastine
Clomipramine
Cocaine
Diphenhydramine
Doxepin
Doxorubicin
Escitalopram
Halofantine
Haloperidol
Hydroxyzine
Levomepromazine
Methadone
Metoclopramide
Mibefradil
Midodrine
Moclobemide
Perphenazine
Ranitidine
Ritonavir
Ticlopidine
Tripelenamine
Inducers of CYP2D6
(Inducers reduce the bioavailabilities of CYP2D6 substrates.)
Rifampin
Dexamethasone
CYP3A4
Substrates of CYP3A4
Alfentanil
Alprazolam
Amlodipine
Aprepitant
Aripiprazole
Atorvastatin
Buspirone
Caffeine
Carbamazepine
Cerivastatin
Chlorpheniramine
Cocaine
Codeine (N-demethylation)
Cyclosporine
Dextromethorphan
Diazepam (3-hydroxylation)
Diltiazem
Erythromycin
Estradiol
Felodipine
Fentanyl
Haloperidol
Hydrocortisone
Indinavir
Lercandipine
Lovastatin
Methadone
Midazolam
Nelfinavir
Nifedipine
Nitrendipine
Ondansetron
Pimozide
Progesterone
Quetiapine
Quinidine (3-hydroxylation)
Risoldipine
Risperidone
Ritonavir
Saquinavir
Sildenafil
Simvastatin
Tacrolimus
Testosterone
Tetrahydrocannabinol
Trazodone
Triazolam
Verapamil
Zaleplon
Ziprasidone
Zolpidem
Inhibitors of CYP3A4
(Inhibitors increase the bioavailabilities of CYP3A4 substrates.)
Strong inhibitors
Indinavir
Nelfinavir
Ritonavir
Saquinavir
Erythromycin
Clarithromycin
Telithromycin
Chloramphenicol
Fluconazole
Itraconazole
Ketoconazole
Suboxone
Aprepitant
Diltiazem
Verapamil
Cimetidine
Grapefruit juice
Nefazodone
Other inhibitors of CYP3A4
Amiodarone
Chloramphenicol
Boceprevir
Toleprevir
Deleviridine
Ciprofloxacin
Norfloxacin
Diethyldithiocarbamate
Fluvoxamine
Gestadene
Imatinib
Carbamazepine
Mifepristone
Voriconazole
Star fruit
Piperine (pepper)
Pomegranate
Noni fruit
Inducers of CYP3A4
(Inducers reduce the bioavailabilities of CYP3A4 substrates.)
Amprenavir
Aprepitant
Armodafinil
Avasimibe
Carbamazepine
Echinacea
Efavirenz
Glucocorticoids
Modafinil
Nafcillin
Nevirapine
Oxcarbazepine
Phenobarbital
Phenytoin
Prednisone
Proglitazone
Rifabutin
Rifampin
Rufinamide
St Johns wort
Troglitazone
CYP2E1
Substrates of CYP2E1
Inhalant anesthetics
Ethyl alcohol
Inhibitors of CYP2E1
(Inhibitors increase the bioavailabilities of CYP2E1 substrates.)
Diethyldithiocarbamate
Disulfiram
Inducers of CYP2E1
(Inducers reduce the bioavailabilities of CYP2E1 substrates.)
Ethyl alcohol
Isoniazid