Cytochrome P450 metabolic enzyme substrates, inhibitors, and inducers (continually updated)

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

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