Drs. Horn and Hansten are both professors of pharmacy at the University of Washington School of Pharmacy. For an electronic version of this article, including references if any, visit www.hanstenandhorn.com.

In previous issues of Pharmacy Times, we have discussed the cytochrome P450 (CYP450) enzymes CYP1A2, CYP2C9, CYP2C19, and CYP2D6 (see www.PharmacyTimes.com/Drug Interactions). In the spirit of saving the best for last, in this issue, we will discuss the most important of all CYP450 enzymes: CYP3A4. It has been estimated that CYP3A4 metabolizes about half of all drugs on the market. Because many other commonly used drugs are moderate-to-potent inhibitors of CYP3A4, it is not surprising that drug toxicity of CYP3A4 substrates due to inhibition of CYP3A4 is relatively common.

CYP3A4 also is sensitive to enzyme induction, and a number of drugs are known to be CYP3A4 inducers. CYP3A4 inducers tend to lower plasma concentrations of CYP3A4 substrates, resulting in reduced efficacy of the substrate. This type of drug interaction is probably more frequent than commonly realized, because reduced drug effect may simply be attributed to lack of patient response.

Many drugs that are CYP3A4 substrates, inhibitors, and inducers are also substrates, inhibitors, or inducers of the ABC transport protein known as P-glycoprotein. Many drug interactions, therefore, involve additive effects of both CYP3A4 and P-glycoprotein.

Table
CYP3A4 Substrates Producing Potentially Serious Toxicity When Combined with CYP3A4 Inhibitors
Drug
Potential Toxicity

Alfuzosin (Uroxatral)

Severe hypotension

Alprazolam (Xanax)

Excessive CNS depression

Budesonide

Cushing's syndrome

Carbamazepine (Tegretol)

Vomiting, headache, dizziness, drowsiness

Colchicine

Fever, diarrhea, muscle pain, paresthesias (may be fatal)

Cyclosporine (eg, Neoral)

Cyclosporine toxicity

Dexamethasone

Cushing's syndrome

Disopyramide (Norpace)

Cardiac arrhythmias

Ergotamine (and other ergot alkaloids)

Ergotism (peripheral ischemia, cyanosis, hypertension)

Fluticasone (Flovent)

Cushing's syndrome

Lovastatin (Mevacor)

Rhabdomyolysis

Methylprednisolone

Cushing's syndrome

Midazolam (oral)

Excessive CNS depression

Pimozide (Orap)

Torsades de pointes

Quinidine

Cardiac arrhythmias

Repaglinide (Prandin)

Hypoglycemia

Rifabutin (Mycobutin)

Uveitis, bone marrow suppression, rash

Sildenafil (Viagra)

Hypotension, syncope

Simvastatin (Zocor)

Rhabdomyolysis

Tadalafil (Cialis)

Hypotension, syncope

Triazolam (Halcion)

Excessive CNS depression

Vardenafil (Levitra)

Hypotension, syncope

Vinblastine (Velban)

Bone marrow suppression

Vincristine (Oncovin)

Peripheral neuropathy, paralytic ileus

CNS = central nervous system.

CYP3A4 Substrates

Drugs metabolized by CYP3A4 are called CYP3A4 substrates. Keep in mind that many drugs are metabolized by more than one CYP450 enzyme, and CYP3A4 may represent only one pathway. Unfortunately, many CYP3A4 substrates have substantial toxicity, and some patients may develop severe toxicity when CYP3A4 inhibitors are taken concurrently. A selected list of such interactions appears in the Table.

CYP3A4 Substrates

Alfentanil (Alfenta)
Alfuzosin (Uroxatral)
Almotriptan (Axert)
Alprazolam (Xanax)
Amiodarone (Cordarone)
Amlodipine (Norvasc)
Aprepitant (Emend)
Atazanavir (Reyataz)
Atorvastatin (Lipitor)
Bepridil (Vascor)
Bexarotene (Targretin)
Bosentan (Tracleer)
Bromocriptine (Parlodel)
Budesonide (Entocort)
Buprenorphine (Subutex)
Bupropion (Zyban, Wellbutrin, Voxra)
Carbamazepine (eg, Tegretol)
Cevimeline (Evoxac)
Cilostazol (Pletal)
Cisapride (Propulsid)
Clarithromycin (Biaxin)
Clonazepam (Klonopin)
Clopidogrel (Plavix)
Colchicine
Cyclophosphamide (Cytoxan)
Cyclosporine (Neoral)
Dapsone (Avlosulfon)
Darunavir (Prezista)
Dasatinib (Sprycel)
Delavirdine (Rescriptor)
Dexamethasone (Decadron)
Dihydroergotamine
Diltiazem (Cardizem)
Disopyramide (Norpace)
Docetaxel (Taxotere)
Donepezil (Aricept)
Doxorubicin (Adriamycin)
Droperidol
Dutasteride (Avodart)
Ebastine (Kestine)
Efavirenz (Sustiva)
Eletriptan (Relpax)
Eplerenone (Inspra)
Ergotamine (Ergomar)
Erlotinib (Tarceva)
Erythromycin
Estazolam (ProSom)
Eszopiclone (Lunesta)
Ethinyl Estradiol
Ethosuximide (Zarontin)
Etoposide (Vepesid)
Exemestane (Aromasin)
Felodipine (Plendil)
Fentanyl (Sublimaze)
Finasteride (Proscar)
Flurazepam (Dalmane)
Fosamprenavir (Lexiva)
Galantamine (Reminyl)
Gefitinib (Iressa)
Granisetron (Kytril)
Halofantrine (Halfan)
Ifosfamide (Ifex)
Imatinib (Gleevec)
Indinavir (Crixivan)
Irinotecan (Camptosar)
Isradipine (DynaCirc)
Itraconazole (Sporanox)

Ixabepilone (Ixempra)
Ketoconazole (Nizoral)
Lapatinib (Tykerb)
Levomethadyl (Orlaam)
Loperamide (Imodium)
Lopinavir (Kaletra)
Loratadine (Claritin)
Lovastatin (Mevacor)
Maraviroc (Selzentry)
Mefloquine (Lariam)
Methylprednisolone
Midazolam (Versed)
Mifepristone (Mifeprex)
Modafinil (Provigil)
Nefazodone
Nevirapine (Viramune)
Nicardipine (Cardene)
Nifedipine (Adalat)
Nimodipine (Nimotop)
Nisoldipine (Sular)
Nitrendipine (Baypress)
Oxybutynin (Ditropan)
Oxycodone (Percodan)
Paclitaxel (Taxol)
Paricalcitol (Zemplar)
Pimozide (Orap)
Pioglitazone
Praziquantel (Biltricide)
Prednisolone
Prednisone
Propoxyphene (Darvon)
Quazepam (Doral)
Quetiapine (Seroquel)
Quinacrine
Quinidine
Quinine
Ranolazine (Ranexa)
Repaglinide (Prandin)
Rifabutin (Rimactane)
Ritonavir (Norvir)
Saquinavir (Invirase)
Sibutramine (Meridia)
Sildenafil (Viagra)
Simvastatin (Zocor)
Sirolimus (Rapamune)
Solifenacin (Vesicare)
Sufentanil (Sufenta)
Sunitinib (Sutent)
Tacrolimus (Prograf)
Tadalafil (Cialis)
Tamoxifen (Nolvadex)
Tamsulosin (Flomax)
Teniposide (Vumon)
Testosterone
Tiagabine (Gabitril)
Tinidazole (Tindamax)
Tipranavir (Aptivus)
Topiramate (Topamax)
Triazolam (Halcion)
Vardenafil (Levitra)
Verapamil (Calan)
Vinblastine (Velbane)
Vincristine (Oncovin)
Ziprasidone (Geodon)
Zolpidem (Ambien)
Zonisamide (Zonegran)
Zopiclone (Imovane)

CYP3A4 Inhibitors

Drugs that inhibit CYP3A4 activity will almost always increase the plasma concentrations of the CYP3A4 substrate medications. Some drugs, such as clarithromycin, itraconazole, and ketoconazole, are particularly potent inhibitors of CYP3A4; patients on these drugs may have markedly reduced CYP3A4 activity.

CYP3A4 Inhibitors

Amiodarone
Amprenavir
Aprepitant
Atazanavir
Chloramphenicol
Clarithromycin
Conivaptan
Cyclosporine
Darunavir
Dasatinib
Delavirdine
Diltiazem
Erythromycin
Fluconazole
Fluoxetine
Fluvoxamine
Fosamprenavir
Grapefruit juice

Imatinib
Indinavir
Isoniazid
Itraconazole
Ketoconazole
Lapatinib
Miconazole
Nefazodone
Nelfinavir
Posaconazole
Ritonavir
Quinupristin
Saquinavir
Tamoxifen
Telithromycin
Troleandomycin
Verapamil
Voriconazole

CYP3A4 Inducers

CYP3A4 inducers are drugs that increase the activity of CYP3A4. Note that the CYP3A4 enzyme is particularly susceptible to enzyme inducers, and marked reductions in the plasma concentrations of CYP3A4 substrates may occur. For example, a patient taking the potent CYP3A4 inducer rifampin may have a roughly 90% reduction in serum concentrations of CYP3A4 substrates, such as buspirone, triazolam, and verapamil.

CYP3A4 Inducers

Aminoglutethimide
Bexarotene
Bosentan
Carbamazepine
Dexamethasone
Efavirenz
Fosphenytoin
Griseofulvin
Modafinil
Nafcillin

Nevirapine
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
Rifabutin
Rifampin
Rifapentine
St. John's wort