CYP P450 Enzymes and Their Inhibitors, Inducers, and Substrates

Terbinafine (Lamisil) taken with Amitriptyline (Elavil® -tricyclic antidepressant)

Terbinafine is CYP2D6 inhibitor Amitriptyline is metabolized by CYP2D6 POSSIBLE CLINICAL EFFECT: Dry mouth, dizziness, and cardiac toxicity caused by *prolonged increase* in amitriptyline and nortriptyline (Pamelor) levels.

POTENT INHIBITORS*

*—These will slow down substrate drug metabolism and increase drug effect.

Amiodarone (Cordarone) with *Warfarin* (Coumadin)

Amiodarone is CYP2C9 and CYP3A4 inhibitor. Warfarin is CYP2C9 substrate. I.e. warfarin is metabolized by CYP2C9. POSSIBLE CLINICAL EFFECT: Increased risk of bleeding caused by increased warfarin level.

Carbamazepine (Tegretol), phenobarbital, phenytoin (Dilantin) taken with Ethinyl estradiol-containing contraceptives.

Carbamazepine, phenobarbital and phenytoin are CYP3A4 inducers Ethinyl estradiol is metabolized by CYP3A4. POSSIBLE CLINICAL EFFECT: Unplanned pregnancy caused by reduced estradiol level.

Clarithromycin (Biaxin), erythromycin, telithromycin (Ketek) taken with Simvastatin (Zocor), verapamil (Calan)

Clarithromycin, erythromycin, telithromycin are CYP3A4 inhibitors. Simvastatin , verapamil metabolized by CYP3A4. POSSIBLE CLINICAL EFFECT: Myopathy or rhabdomyolysis caused by increased simvastatin levels Hypotension and QT interval prolongation caused by increased verapamil levels

Diltiazem (Cardizem), verapamil taken with Prednisone

Diltiazem and verapamil are CYP3A4 inhibitors Prednisone is CYP3A4 substrate and is metabolized by it POSSIBLE CLINICAL EFFECT: Immunosuppression caused by *increased* prednisolone serum levels

Fluoxetine (Prozac), paroxetine (Paxil) taken with Risperidone (Risperdal) or tramadol (Ultram)

Fluoxetine (Prozac), paroxetine (Paxil) are CYP2D6 inhibitors. Risperidon and tramadol are metabolized by CYP2D6 POSSIBLE CLINICAL EFFECT: Increased risk of extrapyramidal adverse effects caused by increased risperidone level; Decrease in analgesic effect caused by low level of active metabolite. Tramadol is a pro-drug. Its metabolite is what causes analgesia.

Grapefruit juice taken with Buspirone (Buspar) N.B. Buspirone is an antianxiety agent that is not chemically or pharmacologically related to the benzodiazepines, barbiturates.

Grapefruit juice is CYP3A4 inhibitor Buspirone is metabolized by CYP3A4 POSSIBLE CLINICAL EFFECT: Dizziness and serotonin syndrome caused by increased buspirone level

Metronidazole (Flagyl) taken with *warfarin*

Metronidazole is CYP2C9 inhibitor Warfarin is metabolized by CYP2C9 POSSIBLE CLINICAL EFFECT: Increased risk of bleeding caused by increased warfarin level

CYP1A2

POTENT INHIBITORS*: Amiodarone (Cordarone), cimetidine (Tagamet), ciprofloxacin (Cipro), fluvoxamine (Luvox‡) POTENT INDUCERS†: Carbamazepine (Tegretol), phenobarbital, rifampin (Rifadin), tobacco SUBSTRATES: Caffeine, clozapine (Clozaril), theophylline

CYP2D6

POTENT INHIBITORS*: Amiodarone, cimetidine, diphenhydramine (Benadryl), fluoxetine, paroxetine (Paxil), quinidine, ritonavir, terbinafine (Lamisil) POTENT INDUCERS†: No significant inducers SUBSTRATES: Amitriptyline, carvedilol, codeine, donepezil (Aricept), haloperidol (Haldol), metoprolol (Lopressor), paroxetine, risperidone (Risperdal), tramadol (Ultram)

CYP2C9

POTENT INHIBITORS*: Amiodarone, fluconazole (Diflucan), fluoxetine (Prozac), metronidazole (Flagyl), ritonavir (Norvir), trimethoprim/sulfamethoxazole (Bactrim, Septra) POTENT INDUCERS†: Carbamazepine, phenobarbital, phenytoin (Dilantin), rifampin SUBSTRATES: *WARFARIN- major substrate* - CYP2C9 Inhibitors (Strong): May decrease the metabolism of CYP2C9 Substrates. Risk D: Consider therapy modification CYP2C9 Inducers (Strong): May increase the metabolism of CYP2C9 Substrates. Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Risk D: Consider therapy modification Carvedilol (Coreg), celecoxib (Celebrex), glipizide (Glucotrol), ibuprofen (Motrin), irbesartan (Avapro), losartan (Cozaar)

CYP3A4 and CYP3A5

POTENT INHIBITORS*: Clarithromycin (Biaxin), diltiazem (Cardizem), erythromycin, grapefruit juice, itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone‡), ritonavir, telithromycin (Ketek), verapamil (Calan) POTENT INDUCERS†: Carbamazepine,Hypericum perforatum (St. John's wort), phenobarbital, phenytoin, rifampin SUBSTRATES: Alprazolam (Xanax), amlodipine (Norvasc), atorvastatin (Lipitor), cyclosporine (Sandimmune), diazepam (Valium), estradiol (Estrace), simvastatin (Zocor), sildenafil (Viagra), verapamil, zolpidem (Ambien)

CYP2C19

POTENT INHIBITORS*: Fluvoxamine, isoniazid (INH), ritonavir POTENT INDUCERS†: Carbamazepine, phenytoin, rifampin SUBSTRATES: Omeprazole (Prilosec), phenobarbital, phenytoin

POTENT INDUCERS†

†—These will speed up substrate drug metabolism and decrease drug effect.