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The Effect of Cytochrome P450 Metabolism on Drug Response


4.4.2018 | Andrew Babcock

Patients should be monitored closely for the development of adverse drug effects or therapeutic failures when a potent CYP450 enzyme inhibitor or inducer is added to drugs metabolized by one or more CYP450 enzymes. C.

This is because drug metabolism via CYP450 enzymes exhibits genetic variability (polymorphism) that influences a patient's response to a particular drug. One out of every 15 white or black persons may have an exaggerated response to standard doses of beta blockers (e.g., metoprolol ), or no response to the analgesic tramadol (Ultram). 3.

CYP = cytochrome P.

Genetic variations in CYP450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. C.

Immunosuppression caused by increased prednisolone serum levels 23.

CYP2C9 and CYP3A4 inhibitor Warfarin (Coumadin) CYP2C9.

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The Effect of Cytochrome P450 Metabolism on Drug Response

Large, prospective trials needed to demonstrate that genotype testing improves outcomes and is cost-effective.

Indiana University School of Medicine drug interaction table ( http://medicine.iupui.edu/flockhart/table.htm ) 16.

C. Because they are known to cause clinically significant CYP450 drug interactions, always use caution when adding the following substances to medications that patients are taking: amiodarone (Cordarone), antiepileptic drugs, antidepressants, antitubercular drugs, grapefruit juice, macrolide and ketolide antibiotics, nondihydropine calcium channel blockers, or protease inhibitors.

The patient's International Normalized Ratio quickly stabilizes. Review of her medications reveals the addition of monthly fluconazole (Diflucan) for recurrent vulvo-vaginal candidiasis. The following clinical scenario describes a case of drug interaction: A 68-year-old white woman taking warfarin, whose condition was previously well controlled on a stable dose, has recently been difficult to anticoagulate to a therapeutic level. The physician recognizes the drug interaction between warfarin and fluconazole as a potential cause and switches the patient to an alternate antifungal agent.

Clarithromycin (Biaxin), erythromycin, ithromycin (Ketek) CYP3A4 inhibitor.

Alprazolam (Xanax), amlodipine (Norvasc), atorvastatin (Lipitor), cyclosporine (Sandimmune), diazepam (Valium), estradiol (Estrace), simvastatin (Zocor), sildenafil (Viagra), verapamil, zolpidem (Ambien) CYP=cytochrome P.

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

CYP = cytochrome P.

Amiodarone, cimetidine, diphenhydramine (Benadryl), fluoxetine, paroxetine (Paxil), quinidine, ritonavir, terbinafine (Lamisil) No significant inducers.

Risperidone (Risperdal), tramadol (Ultram) CYP2D6.

Increased risk of bleeding caused by increased warfarin level 27 Terbinafine (Lamisil) CYP2D6 inhibitor Amitriptyline CYP2D6.

C. Patients should be monitored closely for the development of adverse drug effects or therapeutic failures when a potent CYP450 enzyme inhibitor or inducer is added to drugs metabolized by one or more CYP450 enzymes.

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

CYP2C9 and CYP3A4 inhibitor Warfarin (Coumadin) CYP2C9.

Myopathy or rhabdomyolysis caused by increased simvastatin level 21.

Increased risk of extrapyramidal adverse effects caused by increased risperidone level 24 ; decrease in analgesic effect caused by low level of active metabolite 25 Grapefruit juice CYP3A4 inhibitor Buspirone (Buspar) CYP3A4.

Genetic variations in CYP450 metabolism should be considered when patients exhibit unusual sensitivity or resistance to drug effects at normal doses. C.

Dry mouth, dizziness, and cardiac toxicity caused by prolonged increase in amitriptyline and nortriptyline (Pamelor) levels 28 CYP=cytochrome P.

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

Studies demonstrate a link between adverse effects and variant CYP450 alleles.

Clarithromycin (Biaxin), diltiazem (Cardizem), erythromycin, grapefruit juice, itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone‡), ritonavir, ithromycin (Ketek), verapamil (Calan).

Carbamazepine (Tegretol), phenobarbital, phenytoin (Dilantin) CYP3A4 inducer Ethinyl estradiol-containing contraceptives CYP3A4.

Myopathy or rhabdomyolysis caused by increased simvastatin level 21.

‡— Brand not available in the United States.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, see page323 or /afpsort.xml.

Omeprazole (Prilosec), phenobarbital, phenytoin CYP2D6.

UGT =uridine diphosphate-glucuronosyltransferase; PDA = personal digital assistant.

Unplanned pregnancy caused by reduced estradiol level 20.

C. Genotype testing may predict persons who are poor metabolizers or are nonresponsive to drugs metabolized by CYP450 enzymes.

Caffeine, clozapine (Clozaril), theophylline CYP2C9.

Well-recognized cause of clinically significant drug interactions.

Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins 14.

Fluoxetine (Prozac), paroxetine (Paxil), CYP2D6 inhibitor.

Information from reference 14 and 16.

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

Hypotension and QT interval prolongation caused by increased verapamil level 22 Diltiazem (Cardizem), verapamil CYP3A4 inhibitor Prednisone CYP3A4.

Comprehensive guide to drug interactions with useful charts and representative cases.

Information from references 10 and 14 through 16 CYP1A2.

Fluvoxamine, isoniazid (INH), ritonavir Carbamazepine, phenytoin, rifampin.

Particularly true if substrate drug depends on only one CYP450 enzyme for metabolism.

Amitriptyline, carvedilol, codeine, donepezil (Aricept), haloperidol (Haldol), metoprolol (Lopressor), paroxetine, risperidone (Risperdal), tramadol (Ultram) CYP3A4 and CYP3A5.

TOM LYNCH, PharmD, AMY PRICE, MD, Eastern Virginia Medical School, Norfolk, Virginia.

Hypotension and QT interval prolongation caused by increased verapamil level 22 Diltiazem (Cardizem), verapamil CYP3A4 inhibitor Prednisone CYP3A4.

Amiodarone, fluconazole (Diflucan), fluoxetine (Prozac), metronidazole (Flagyl), ritonavir (Norvir), trimethoprim/sulfamethoxazole (Bactrim, Septra).

A specific gene encodes each CYP450 enzyme. Finally, some persons inherit multiple copies of wild-type alleles, which results in excess enzyme activity. Alleles are referred to as “wild type” or “variant,” with wild type occurring most commonly in the general population. Polymorphism occurs when a variant allele replaces one or both wild-type alleles. An “extensive” (i.e., normal) metabolizer has received two copies of wild-type alleles. 1 Persons with two copies of variant alleles are “poor” metabolizers, whereas those with one wild-type and one variant allele have reduced enzyme activity. Variant alleles usually encode a CYP450 enzyme that has reduced or no activity. 4. Every person inherits one genetic allele from each parent. This phenotype is termed an “ultrarapid” metabolizer.

Caffeine, clozapine (Clozaril), theophylline CYP2C9.

Fluoxetine (Prozac), paroxetine (Paxil), CYP2D6 inhibitor.

Large, prospective trials needed to demonstrate that genotype testing improves outcomes and is cost-effective.

Amitriptyline, carvedilol, codeine, donepezil (Aricept), haloperidol (Haldol), metoprolol (Lopressor), paroxetine, risperidone (Risperdal), tramadol (Ultram) CYP3A4 and CYP3A5.

Indiana University School of Medicine drug interaction table ( http://medicine.iupui.edu/flockhart/table.htm ) 16.

Alprazolam (Xanax), amlodipine (Norvasc), atorvastatin (Lipitor), cyclosporine (Sandimmune), diazepam (Valium), estradiol (Estrace), simvastatin (Zocor), sildenafil (Viagra), verapamil, zolpidem (Ambien) CYP=cytochrome P.

Severe toxicity can result if CYP450 enzyme–inhibiting drugs are added to the following medications: atypical antipsychotics, benzodiazepines, cyclosporine (Sandimmune), statins, or warfarin (Coumadin). C.

Carbamazepine (Tegretol), phenobarbital, rifampin (Rifadin), tobacco.

2. They also are necessary for the detoxification of foreign chemicals and the metabolism of drugs. There are more than 50 CYP450 enzymes, but the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4, and CYP3A5 enzymes metabolize 90 percent of drugs. CYP450 enzymes are so named because they are bound to membranes within a cell (cyto) and contain a heme pigment (chrome and P) that absorbs light at a wavelength of 450 nm when exposed to carbon monoxide. Cytochrome P450 (CYP450) enzymes are essential for the production of cholesterol, steroids, prostacyclins, and thromboxane A 2. 1, 2 These enzymes are predominantly expressed in the liver, but they also occur in the small intestine (reducing drug bioavailability), lungs, placenta, and kidneys.

Risperidone (Risperdal), tramadol (Ultram) CYP2D6.

Dizziness and serotonin syndrome caused by increased buspirone level 26 Metronidazole (Flagyl) CYP2C9 inhibitor Warfarin CYP2C9.

Ritonavir (Norvir), a protease inhibitor and potent CYP3A4 inhibitor, is added to lopinavir (Kaletra) to boost serum levels in patients with human immunodeficiency virus. Additionally, a drug can be both metabolized by and inhibit the same enzyme (e.g., erythromycin), or it can be metabolized by one enzyme and inhibit another enzyme (e.g., terbinafine ). 14. 18 Drugs may be intentionally combined to take advantage of CYP450 inhibition.

Carvedilol (Coreg), celecoxib (Celebrex), glipizide (Glucotrol), ibuprofen (Motrin), irbesartan (Avapro), losartan (Cozaar) CYP2C19.

Dizziness and serotonin syndrome caused by increased buspirone level 26 Metronidazole (Flagyl) CYP2C9 inhibitor Warfarin CYP2C9.

Carvedilol (Coreg), celecoxib (Celebrex), glipizide (Glucotrol), ibuprofen (Motrin), irbesartan (Avapro), losartan (Cozaar) CYP2C19.

Continually updated table of important substrates, inhibitors, and inducers with direct links from each drug name to a PubMed list of citations.

Concise Guide to Drug Interaction Principles for Medical Practice: Cytochrome P450s, UGTs, P-glycoproteins 14.

Unlike metabolic inhibition, there is usually a delay before enzyme activity increases, depending on the half-life of the inducing drug. Carbamazepine (Tegretol), a potent enzyme inducer, must be initiated at a low dose and then increased at weekly intervals as its half-life gradually decreases over time. Inducers increase CYP450 enzyme activity by increasing enzyme synthesis. 10 A drug also may be metabolized by the same CYP450 enzyme that it induces. A decrease in the concentration of a drug metabolized by CYP2C9 can occur within 24 hours after the initiation of rifampin (Rifadin), an inducer with a short half-life, but can occur up to one week after the initiation of phenobarbital, an inducer with a very long half-life.

Related Editorial. Am Fam Physician. 2007 Aug 1;76(3):391-396.

This PDA software includes a section on cytochrome P450 enzyme activity for each drug narrative.

Clarithromycin (Biaxin), diltiazem (Cardizem), erythromycin, grapefruit juice, itraconazole (Sporanox), ketoconazole (Nizoral), nefazodone (Serzone‡), ritonavir, ithromycin (Ketek), verapamil (Calan).

Drugs section in the Lexi-Complete PDA software package from Lexi-Comp.

View/Print Table. Information from references 19 through 28.

Comprehensive guide to drug interactions with useful charts and representative cases.

For information about the SORT evidence rating system, see page323 or /afpsort.xml. A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series.

Carbamazepine (Tegretol), phenobarbital, phenytoin (Dilantin) CYP3A4 inducer Ethinyl estradiol-containing contraceptives CYP3A4.

Amiodarone (Cordarone). Information from references 19 through 28.

Amiodarone, fluconazole (Diflucan), fluoxetine (Prozac), metronidazole (Flagyl), ritonavir (Norvir), trimethoprim/sulfamethoxazole (Bactrim, Septra).

John's wort), phenobarbital, phenytoin, rifampin. Carbamazepine, Hypericum perforatum (St.

Increased risk of bleeding caused by increased warfarin level 19.

‡— Brand not available in the United States.

Increased risk of bleeding caused by increased warfarin level 19.

Immunosuppression caused by increased prednisolone serum levels 23.

Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes. Cytochrome P450 enzymes are essential for the metabolism of many medications. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes.

Dry mouth, dizziness, and cardiac toxicity caused by prolonged increase in amitriptyline and nortriptyline (Pamelor) levels 28 CYP=cytochrome P.

Unplanned pregnancy caused by reduced estradiol level 20.

Are either potent inhibitors or inducers of CYP450 enzymes.

Studies demonstrate a link between adverse effects and variant CYP450 alleles.

Clarithromycin (Biaxin), erythromycin, ithromycin (Ketek) CYP3A4 inhibitor.

3 View/Print Table. 7, 8 One in five Asian persons is a poor metabolizer of drugs dependent on CYP2C19, which metabolizes phenytoin (Dilantin), phenobarbital, omeprazole (Prilosec), and other drugs. 4 – 6 For example, 7 percent of white persons and 2 to 7 percent of black persons are poor metabolizers of drugs dependent on CYP2D6, which metabolizes many beta blockers, antidepressants, and opioids. 9 Variance in drug response among persons of different ethnic origins also can be caused by genetic variations in other drug-metabolizing enzymes, drug transporters, and drug receptors. CYP450 enzyme polymorphism is responsible for observed variations in drug response among patients of differing ethnic origins.

Simvastatin (Zocor), verapamil (Calan) CYP3A4.

Carbamazepine, Hypericum perforatum (St. John's wort), phenobarbital, phenytoin, rifampin.

Simvastatin (Zocor), verapamil (Calan) CYP3A4.

C. Severe toxicity can result if CYP450 enzyme–inhibiting drugs are added to the following medications: atypical antipsychotics, benzodiazepines, cyclosporine (Sandimmune), statins, or warfarin (Coumadin).

Carbamazepine (Tegretol), phenobarbital, rifampin (Rifadin), tobacco.

The FDA has required this information for every drug approved since 1997. View/Print Table Amiodarone (Cordarone). As shown in this example, physicians should be cautious when prescribing a drug known to be a CYP450 inhibitor or inducer. Table 3 14, 16 lists some useful CYP450 drug interaction resources. Food and Drug Administration (FDA) or manufacturer's Web sites. The target drug may need to be substituted or the dose adjusted to account for a potential decrease or increase in metabolism. Information regarding a drug's CYP450 metabolism and its potential for inhibition or induction can be found on the drug label and accessed through the U.S. Table 2 19 – 28 lists examples of common drug-drug interactions and their potential clinical effects.

Omeprazole (Prilosec), phenobarbital, phenytoin CYP2D6.

Genotype testing may predict persons who are poor metabolizers or are nonresponsive to drugs metabolized by CYP450 enzymes. C.

Amiodarone (Cordarone), cimetidine (Tagamet), ciprofloxacin (Cipro), fluvoxamine (Luvox‡).

Carbamazepine, phenobarbital, phenytoin (Dilantin), rifampin.

Many drug interactions are the result of an alteration of CYP450 metabolism. market because metabolic inhibition by other drugs led to life-threatening arrhythmias. market in 1998 because it was a potent enzyme inhibitor that resulted in toxic levels of other cardiovascular drugs. 12. 10 The non-sedating antihistamines terfenadine (Seldane) and astemizole (Hismanal), and the gastrointestinal motility agent cisapride (Propulsid), were all withdrawn from the U.S. 11 The calcium channel blocker mibefradil (Posicor) was withdrawn from the U.S.

Continually updated table of important substrates, inhibitors, and inducers with direct links from each drug name to a PubMed list of citations.

Information from references 10 and 14 through 16.

Increased risk of extrapyramidal adverse effects caused by increased risperidone level 24 ; decrease in analgesic effect caused by low level of active metabolite 25 Grapefruit juice CYP3A4 inhibitor Buspirone (Buspar) CYP3A4.

Drugs interact with the CYP450 system in several ways. Inhibitors block the metabolic activity of one or more CYP450 enzymes. View/Print Table CYP1A2. 17 Inhibitory effects usually occur immediay. Drugs may be metabolized by only one CYP450 enzyme (e.g., metoprolol by CYP2D6) or by multiple enzymes (e.g., warfarin by CYP1A2, CYP2D6, and CYP3A4). 13 Drugs that cause CYP450 metabolic drug interactions are referred to as either inhibitors or inducers ( Table 1 10, 14 – 16 ). For instance, sertraline (Zoloft) is considered a mild inhibitor of CYP2D6 at a dose of 50 mg, but if the dose is increased to 200 mg, it becomes a potent inhibitor. The extent to which an inhibitor affects the metabolism of a drug depends upon factors such as the dose and the ability of the inhibitor to bind to the enzyme.

Because they are known to cause clinically significant CYP450 drug interactions, always use caution when adding the following substances to medications that patients are taking: amiodarone (Cordarone), antiepileptic drugs, antidepressants, antitubercular drugs, grapefruit juice, macrolide and ketolide antibiotics, nondihydropine calcium channel blockers, or protease inhibitors. C.

Fluvoxamine, isoniazid (INH), ritonavir Carbamazepine, phenytoin, rifampin.

Amiodarone (Cordarone), cimetidine (Tagamet), ciprofloxacin (Cipro), fluvoxamine (Luvox‡).

Well-recognized cause of clinically significant drug interactions.

Carbamazepine, phenobarbital, phenytoin (Dilantin), rifampin.

Increased risk of bleeding caused by increased warfarin level 27 Terbinafine (Lamisil) CYP2D6 inhibitor Amitriptyline CYP2D6.

Are either potent inhibitors or inducers of CYP450 enzymes.

Particularly true if substrate drug depends on only one CYP450 enzyme for metabolism.

Amiodarone, cimetidine, diphenhydramine (Benadryl), fluoxetine, paroxetine (Paxil), quinidine, ritonavir, terbinafine (Lamisil) No significant inducers.

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