Get to Know an Enzyme: CYP3A4

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Pharmacy Times, Volume 0,0

The last in the series of cytochrome P450 enzyme articles ends with the most important enzyme-CYP3A4, which metabolizes approximately half of all the drugs on the market.

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