Top 300 Pharmacy Drug Cards

Preface H: Guide to Cytochrome P450 (CYP) and UGT1A1 Metabolism

Definitions

Inhibitors

• Strong inhibitor is one that causes a ≥5-fold increase in the plasma AUC values or more than 80% decrease in clearance.

• Moderate inhibitor is one that causes a ≥2-fold but <5-fold increase in the plasma AUC values or 50-79% decrease in clearance.

• Weak inhibitor is one that causes a >1.25-fold but <2-fold increase in the plasma AUC values or 20-49% decrease in clearance.

Inducers

• Strong inducer is one that causes a ≥80% decrease in the plasma AUC.

• Moderate inducer is one that causes a 50-79% decrease in plasma AUC.

• Weak inducer is one that causes a 20-49% decrease in plasma AUC.

Substrates

• Sensitive substrates are when ≥25% of metabolism occurs via a given enzyme.

• Non-sensitive substrates are when <25% of metabolism occurs via a given enzyme.

Clinical Implications

Assessment and clinical management of drug–drug interaction:

1. Are both drugs systemically absorbed? If no, no drug interaction.

2. Do both drugs impact the same enzyme system? If not, no drug interaction.

3. The majority of clinically significant drug interactions involve and enzyme inducer or inhibitor and a sensitive substrate (which is metabolized by the enzyme). For example, itraconazole is a strong inhibitor of CYP3A4/5. Amiodarone is a sensitive substrate. Giving them together may result in higher amiodarone levels and toxicity. Clinical management would be to select an alternative antifungal, of dose reduce amiodarone. Strong inducers increase metabolism and decrease efficacy of substrates. Clinical management would be to select an alternative agent or increase the dose of the substrate.

4. Some drugs are prodrugs. For example, itraconazole is a strong inhibitor of CYP3A4/5. Cyclophosphamide is a sensitive substrate that is activated to acrolein by CYP3A4/5. Giving them together may result in lower acrolein levels and loss of efficacy. Clinical management would be to select an alternative antifungal. Strong inducers, like carbamazepine, increase metabolism and have higher acrolein levels. Clinical management would be to select an alternative agent or decrease the dose of the cyclophosphamide.

CYP1A2

Inhibitors (Strong). Caffeine, ciprofloxacin, enoxacin, fluvoxamine, ketoconazole, lidocaine, methoxselan, mexilitine, norfloxacin, ofloxacin, primaquine, thiabendazole

Inhibitors (Moderate). Amlodipine, cimetidine, diclofenac, fluoxetine, fospropofol, gemfibrozil, miconazole, nifedipine, propofol, zileuton

Inducers. Aminoglutethimide, carbamazepine, phenobarbital, primadone, rifampin

Substrates (Sensitive). Acenocoumarol, aminophylline, betaxolol, caffeine, clomipramine, clozapine, cyclobenzaprine, dacarbazine, doxepin, duloxetine, estrogens, flutamide, fluvoxamine, mexiletine, mirtazapine, pimozide, propranolol, riluzole, ropinorole, tacrine, theophylline, thiothixene, trifluoperazine

CYP2A6

Inhibitors (Strong). Letrozole, methoxselan, miconazole, tranlcypromine

Inhibitors (Moderate). Amiodarone, desipramine, isoniazid, ketoconazole

Inducers. Amobarbital, pentobarbital, phenobarbital, rifampin, secobarbital

Substrates (Sensitive). Dexmedetomidine

CYP2B6

Inhibitors (Strong). None

Inhibitors (Moderate). Doxorubicin, paroxetine, sorafenib

Inducers. Carbamazepine, phenobarbital, phenytoin, rifampin

Substrates (Sensitive). Buprorpion, cyclophosphamide (activated to acrolein by CYP2B6), efavirenz, irinotecan, ketamine, promethazine, propofol, selegiline

CYP2C8

Inhibitors (Strong). Atorvastatin, gemfibrozol, ritonavir

Inhibitors (Moderate). Celocoxib, felodipine, fenofibrate, ibesartan, losarten, pioglitazone, quine, rabapezole, rosiglitazone, tamoxifen, trimethroprim

Inducers. Carbamazepine, phenobarbital, phenytoin, primodone, rifampin, secobarbital

Substrates (Sensitive). Amitryptiline, mestranol (activated by CYP2C8 to ethinyl estradiol), paclitaxel, pioglitazone, rifabutin, rosuvastatin, tretinoin

CYP2C9

Inhibitors (Strong). Delaviridine, flubiprofen, fluconazole, ibuprofen, indomethacin, isoniazid, mefenamic acid, miconazole, nicardipine, sulfadiazine, sulfasoxazole, tolbutamide

Inhibitors (Moderate). Amiodarone, efavirenz, fenofibrate, fluvastatin, gemfibrozil, irbesartan, ketoconazole, losartan, omeprazole, pantoprazole, pyrimethamine, quinine, sorafenib, sulfamethoxasole, trimethoprim, warfarin, zarfirlukast

Inducers. Carbamazepine, phenobarbital, phenytoin, primodone, rifampin, rifapentine, secobarbital

Substrates (Sensitive). Alprazolam, bosenten, carvedilol, celocoxib, dapsone, fluoxetine, glimeride, glipizide, ketamine, losartan, mestranol (activated by CYP2C9 to ethinyl estradiol), montelukast, paclitaxel, phenytoin, propofol, sulfadiazine, sulfa-methoxasole, sulfasoxazole, sulfinpyrazone, tamoxifen, tolbutamide, toresmide, trimethoprim, voriconazole, warfarin, zafirlukast, zopiclone

CYP2C19

Inhibitors (Strong). Delaviridine, fluconazole, fluoxetine, fluvoxamine, gemfibrozil, ketoconazole, miconazole, modafinil, omeperazole, piroxicam, ticlodipine

Inhibitors (Moderate). Bortezomib, cimetidine, efavirenz, esomeprazole, fospropofol, lansoprazole, loratidine, nicardipine, propofol, rabeprazole, sertraline

Inducers. Aminoglutethimide, carbamazapine, phenytoin, rifampin

Substrates (Sensitive). Carisoprodol, citralopram, clobazam, clomipramine, diazepam, escitralopram, esomeprazole, imipra-mine, lansoprazole, methsuximide, moclobramide, nelfinavir, nilutamide, omeprazole, pantoprazole, pentamidine, phenobarbital, phenytoin, progesterone, rabeprazole, ranitidine, sertraline, trimipramine, voriconazole

CYP2D6

Inhibitors (Strong). Chlorpromazine, cinacalet, cocaine, delaviridine, dexmedetomidine, dextromethorphan, fluoxetine, miconazole, paroxetine, pergolide, quinidine, ritonovir, ropirinole, terbinafine, quinine

Inhibitors (Moderate). Amiodarone, chloroquine, cimetidine, clomipramine, clozapine, darifenacin, desipramine, diphenhydramine, duloxetine, haloperidol, imipramine, isoniazid, lidocaine, methadone, mithimazole, nicardipine, pioglitazone, pyrimethamine, quinine, ranolazine, sertraline, thioridazine, ticlopidine, trazadone

Inducers. None

Substrates (Sensitive).

• Antibiotics: Chloroquine, doxycycline

• Cardiovascular: Atorvastatin, betaxolol, captorpil, carvedilol, flecainide, lidocaine, metoprolol, mexiltine, pindolol, propafe-none, propranolol, timolol

• CNS: Amitryptiline, amphetamine, amoxapine, aripipazole, chlorpromazine, clomipramine, desipramine, dextroamphetamine, dextromethorphan, dihydroergotamine, duloxetine, fluoxetine, flurazepam, fluvoxamine, haloperidol, imipramine, methylphenidate, mirtazepine, moclobemide, norfazidone, nortriptyline, paroxetine, perphenazine, promethazine, risperi-done, sertraline, thioridazine, tramadol, trimipramine, venlafaxine

• Pain: Codeine (activated by CYP2D6 to morphine), oxycodone

• Oncology: Doxorubicin, lomustine, tamoxifen

• Misc: Hydrocortisone, lansoprazole, tamulosin

CYP2E1

Inhibitors (Strong). Disulfiram

Inhibitors (Moderate). Isoniazid, miconazole

Inducers. None

Substrates (Sensitive). Chlorzoxazone, dacarbazine, halothane, isoflurane, isoniazid, sevoflurane, theophylline, trimethadione

CYP3A4/5

Inhibitors (Strong). Altanavir, amprenavir/fosamprenavir, clarithromycin, conivapten, delaviridine, enoxacin, imatinib, indinavir, isoniazid, itraconazole, ketoconazole, miconazole, nefazadone, nelfinavir, nicardipine, propofol, ritonovir, telithromycin

Inhibitors (Moderate). Amiodarone, aprepitant, cimetidine, clotrimazole, desipramine, dexamethasone, diltiazem, doxycycline, erythromycin, fluconazole, isoniazid, lidocaine, metronidazole, miconazole, norfloxacin, sertraline, tetracycline, vera-pamil, voriconazole

Inducers. Aminoglutethimide, carbamazapine/oxcarbezapine, nevirapine, phenobarbital, phenytoin, pentobarbital/primadone, rifabutin, rifampin

Substrates (Sensitive)

• Acid blockers: Cisapride, lansoprazole, omeprazole, rabepazole

• Antibiotics: Chloroquine, clarithromycin, doxycycline, erythromycin, mefloquine, telithromycin, tetracycline, trimethoprim,

spiramycin

• Antifungals: Itraconazole, ketoconazole, miconazole

• Antihistamines: Azelastine, cerivistatin, chlorpheniramine

• Cardiovascular: Amiodarone, bosenten, budesonide, cilostazol, diltiazem, disopyramide, enalapril, felodipine, isosorbide, isradipine, lidocaine, losartan, lovastatin, moricizine, nicardipine, nifedipine, nimodipine, nisoldipine, quinidine, simvastatin, ticlodipine

• CNS: Alprazolam, amoxapine, benztropine, buprenorphine, buspirone, carisoprodol, chlorazapate, chlordiazepoxide, clobazam, clonazepam, cocaine, dantrolene, diazepam, dihydroergotamine, doxepin, eletriptan, escitralopram, ethosuximide, felbamate, flurazepam, haloperidol, mirtazapine, modafinil, pergolide, phencyclidine, pimozide, quetiapine, ranolazine, traza-done, tiagabine, triazolam

• HIV: Amprenavir, atanzavir, delavirdine, efevirenz, indinavir, nefazadone, nelfinavir, nevirapine, primaquine, rifabutin, ritonavir, saquinavir, tipranavir

• Hormones/Steroids: Estrogens, exemestane, flutamide, fluticasone, letrozole, medroxyprogesterone, mestranol, progesterone, toremifine

• Immunosuppressants: Cyclosporine, dapsone, sirolimus, tacrolimus

• Oncology: Bortezomib, busulfan, cyclophosphamide (activated to acrolein by CYP3A4/5), docetaxel, doxorubicin, etopo-side, ifosfamide (activated to acrolein by CYP3A4/5), imatinib, irinotecan, palcitaxel, sorafenib, sunitinib, tenisposide

• Pain/Sedation: Alfentanil, fentanyl, ketamine, methadone, midazolam, sufentanil

• Pulmonary: Albuterol, montelukast, salmeterol, theophylline

• Misc: Aprepitant, brinzolamide, bromocriptine, colchicine, conivaptan, nateglinide, repiglinide, sibutramine, sildenafil, tamsulosin