Cytochrome P450: New Nomenclature and Clinical Implications

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Cytochrome P450: New Nomenclature and Clinical Implications

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MELANIE JOHNS CUPP, PHARM.D., and TIMOTHY S. TRACY, PH.D.

West Virginia University School of Pharmacy, Morgantown, West Virginia

 

Many drug interactions are a result of inhibition or induction of cytochrome

P450 enzymes (CYP450). The CYP3A subfamily is involved in many clinically

significant drug interactions, including those involving nonsedating

antihistamines and cisapride, that may result in cardiac dysrhythmias. CYP3A4

and

CYP1A2 enzymes are involved in drug interactions involving theophylline. CYP2D6

is

responsible for the metabolism of many psychotherapeutic agents. The

protease inhibitors, which are used to treat patients infected with the human

immunodeficiency virus, are metabolized by the CYP450 enzymes and consequently

interact with a multitude of other medications. By understanding the unique

functions and characteristics of these enzymes, physicians may better

anticipate

and manage drug interactions and may predict or explain an individual's

response to a particular therapeutic regimen.

The basic purpose of drug metabolism in the body is to make drugs more water

soluble and thus more readily excreted in the urine or bile.1,2 One common

way of metabolizing drugs involves the alteration of functional groups on the

parent molecule (e.g., oxidation) via the cytochrome P450 enzymes. These

enzymes are most predominant in the liver but can also be found in the

intestines, lungs and other organs.3-6 These cytochrome P450 enzymes are

designated by

the letters " CYP " followed by an Arabic numeral, a letter and another Arabic

numeral (e.g., CYP2D6).7 Each enzyme is termed an isoform since each derives

from a different gene. It should be noted, however, that structural

similarity of enzymes cannot be used to predict which isoforms will be

responsible for

a drug's metabolism.

Drug interactions involving the cytochrome P450 isoforms generally result

from one of two processes, enzyme inhibition or enzyme induction. Enzyme

inhibition usually involves competition with another drug for the enzyme

binding

site. This process usually begins with the first dose of the inhibitor,8,9 and

onset and offset of inhibition correlate with the half-lives of the drugs

involved.9 Until genetic tests for isoform expression become

available,

a physician can often anticipate drug interactions in a patient by knowing

which medications inhibit or induce P450 enzymes.SSRIs and cimetidine inhibit

metabolism of tricyclic antidepressants, but the clinical significance of

this finding depends on individual genetic variations and concomitant

medications.

Enzyme induction occurs when a drug stimulates the synthesis of more enzyme

protein,9 enhancing the enzyme's metabolizing capacity. It is somewhat

difficult to predict the time course of enzyme induction because several

factors,

including drug half-lives and enzyme turnover, determine the time course of

induction.

Illustrative Case 1

 

A 74-year-old woman with insulin-dependent (type 2) diabetes had been taking

metoprolol and warfarin for atrial fibrillation and amitriptyline, 50 mg at

bedtime, for diabetic neuropathy, for several years. On the death of her

husband, she presented with symptoms of depression, and paroxetine was added to

her medication regimen with the rationale that paroxetine would cause fewer

side effects than an increase in the amitriptyline dosage. Three days after the

initiation of paroxetine therapy, the woman was brought to the emergency

department by her daughter, who had found her asleep at 11 a.m. On awakening,

the patient complained of dry mouth and dizziness. The emergency department

physician, noting that paroxetine had recently been added to the medication

regimen, changed the patient to fluoxetine, which he thought would be less

sedating. Three days later, the patient was still very sedated and dizzy, and

complained of difficulty urinating. She was again brought to the emergency

department, where bladder catheterization yielded two liters of dark urine. Her

International Normalized Ratio (INR) was 4.0. SSRIs and cimetidine

inhibit metabolism of tricyclic antidepressants, but the clinical significance

of

this finding depends on individual genetic variations and concomitant

medications.

On discussion with a colleague, the emergency department physician learned

that both paroxetine and fluoxetine can inhibit cytochrome P450 enzymes

(isoforms) responsible for the metabolism of the patient's other medications.

This

example illustrates the need to understand the cytochrome P450 isoforms

responsible for drug metabolism and their inhibitors and inducers.

Cytochrome P450 Isoforms

CYP2D6

CYP2D6 has been studied extensively because it exhibits genetic

polymorphism, meaning that distinct population differences are apparent in its

expression

or activity. Approximately 7 to 10 percent of Caucasians are poor

metabolizers of drugs metabolized by CYP2D6.10 Individuals with normal CYP2D6

activity

are termed extensive metabolizers. Ethnic differences are indicated in this

genetic polymorphism, since Asians and blacks are less likely than Caucasians

to be poor metabolizers.11,12 Poor metabolizers are at risk for drug

accumulation and toxicity from drugs metabolized by this isoform. For example,

one

patient who suffered cardiotoxicity induced by desipramine (Norpramin) was

found to be a poor metabolizer.13 Poor metabolizers of CYP2D6 substrates are at

risk for postural hypotension and antipsychotic side effects such as

oversedation, because several antipsychotic agents are metabolized by CYP2D6.14

In a

study of 45 elderly patients (five of whom were poor metabolizers) receiving

perphenazine, side effects increased fivefold in the poor metabolizers

compared with the extensive metabolizers.15 Conversely, when formation of an

active

metabolite is essential for drug action, poor metabolizers of CYP2D6 can

exhibit less response to drug therapy compared with extensive metabolizers.

Codeine is O-demethylated to morphine by CYP2D6, which accounts at least

partially for its analgesic effect.16 Thus, poor metabolizers may have less

response

to codeine than other persons. The substrates and inhibitors of CYP2D6 are

listed in Table 1.

Psychotherapeutic Agents. Many antidepressants are metabolized by CYP2D6,

but other cytochrome P450 isoforms can also contribute to their metabolism

(Tables 1 through 6). The clinical importance of this " dual metabolism " will be

illustrated later. With respect to drugs inhibiting CYP2D6, cimetidine

(Tagamet), the selective serotonin reuptake inhibitors (SSRIs) and some

tricyclic

antidepressants function as inhibitors of this P450 isoform.17-19 Of the

antidepressants, paroxetine (Paxil) appears to have the greatest ability to

inhibit

the metabolism of CYP2D6 substrates. This is followed by fluoxetine (Prozac)

and norfluoxetine; sertraline (Zoloft) and desmethylsertraline; fluvoxamine

(Luvox), nefazodone (Serzone) and venlafaxine (Effexor); clomipramine

(Anafranil), and amitriptyline (Elavil).19 This ranking is based on in vitro

data,

however, and the choice of an antidepressant should be based on factors other

than the propensity to inhibit CYP2D6. Although sertraline appears to be less

likely than the other SSRIs to inhibit CYP2D6, inhibition may still occur at

doses greater than 50 mg. The clinical significance of the inhibition of

tricyclics by SSRIs or cimetidine is subject to variation in enzyme activity

between individuals, the degree to which the patient metabolizes and

co-ingestion of other enzyme inhibitors.20

CYP3A

Inhibitors of CYP3A. Members of the CYP3A subfamily are the most abundant

cytochrome enzymes in humans. They account for 30 percent of the cytochrome

P450 enzymes in the liver21 and are also substantially expressed in the

intestines. Members of this subfamily are involved in many clinically important

drug

interactions.1 Substrates, inhibitors and inducers of CYP3A are listed in

Table 2.

Nonsedating Antihistamines. High plasma concentrations of terfenadine

(Seldane) and astemizole (Hismanal) have been associated with torsade de

pointes, a

life-threatening cardiac arrhythmia characterized by altered cardiac

repolarization and a prolonged QT interval.22 Terfenadine is a prodrug that

undergoes complete first-pass metabolism to an active carboxymetabolite.23 It

is

therefore unusual to detect terfenadine in the plasma of patients who take this

drug at the recommended dosage. Since it is terfenadine rather than its active

metabolite that is cardiotoxic, arrhythmias occur when a build-up of parent

terfenadine takes place. This may occur when azole antifungal medications or

macrolide antibiotics are taken concomitantly.22,24 To counteract this

problem, fexofenadine (Allegra), the active metabolite of terfenadine, is now

marketed as a noncardiotoxic alternative to terfenadine. Like fexofenadine,

loratadine (Claritin) does not appear to be cardiotoxic and thus is also a safe

nonsedating antihistamine alternative.25 TABLE 1

Substrates and inhibitors of CYP2D6

Substrates

Antidepressants*

Amitriptyline (Elavil)

Clomipramine (Anafranil)

Desipramine (Norpramin)

Doxepin (Adapin, Sinequan)

Fluoxetine (Prozac)

Imipramine (Tofranil)

Nortriptyline (Pamelor)

Paroxetine (Paxil)

Venlafaxine (Effexor)

Antipsychotics

Haloperidol (Haldol)

Perphenazine (Etrafon, Trilafon)

Risperidone (Risperdal)

Thioridazine (Mellaril)

Beta blockers

Metoprolol (Lopressor)

Penbutolol (Levatol)

Propranolol (Inderal)*

Timolol (Blocadren)

Narcotics

Codeine, tramadol (Ultram)

Inhibitors

Antidepressants

Paroxetine > fluoxetine >

sertraline (Zoloft) > fluvoxamine

(Luvox),

Nefazodone (Serzone),

Venlafaxine > clomipramine

(Anafranil) > amitriptyline

Cimetidine (Tagamet)

Fluphenazine (Prolixin)

Antipsychotics

Haloperidol

Perphenazine

Thioridazine

 

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*--Other enzymes are also involved.

NOTE: Inhibitors will decrease metabolism of substrates and generally lead

to increased drug effect (unless the substrate is a prodrug). Inducers will

increase metabolism of substrates and generally lead to decreased drug effect

(unless the substrate is a prodrug).

Ketoconazole (Nizoral), itraconazole (Sporanox) and fluconazole (Diflucan)

inhibit CYP3A, although ketoconazole and itraconazole are more inhibiting than

fluconazole.26 Based on in vitro and in vivo studies, ketoconazole and

itraconazole markedly inhibit metabolism of terfenadine, causing changes in the

QT

interval.22,27 At dosages of 200 mg daily, fluconazole did not result in

accumulation of parent terfenadine or changes in the QT interval.28 However, an

interaction with terfenadine and fluconazole coadministration may occur in

patients taking higher dosages of fluconazole or in patients with risk factors

for ventricular arrhythmia. These two drugs should be used together with

caution.

In addition to the azole antifungal medications, the macrolide antibiotics

can also inhibit terfenadine metabolism, resulting in the development of

torsade de pointes. Erythromycin and clarithromycin (Biaxin) have been shown to

alter terfenadine metabolism, but this does not appear to occur with

azithromycin (Zithromax).29 Thus, a patient who is taking terfenadine and needs

macrolide antibiotic therapy should be given azithromycin to avoid possible

cardiac

consequences.

The SSRIs are 28 to 775 times less potent as inhibitors of terfenadine

metabolism than ketoconazole.30 With respect to ability to inhibit CYP3A, the

following order of the SSRIs is observed: nefazodone is greater than

fluvoxamine,

and norfluoxetine is greater than fluoxetine, which is greater than

sertraline, desmethylsertraline, paroxetine and venlafaxine.31 Several

clinically

important cardiac events have been reported in patients receiving fluoxetine or

fluvoxamine with terfenadine or astemizole.30,32,33 The use of fluvoxamine or

nefazodone with terfenadine or astemizole is contraindicated, and the U.S.

Food and Drug Administration is currently considering requiring a

contraindication against the use of other SSRIs with the nonsedating

antihistamines.30

The package insert for sertraline contains a warning against its use with

terfenadine and astemizole.34 In patients who need to take an antidepressant

and a

nonsedating antihistamine concurrently, paroxetine, venlafaxine and

tricyclic antidepressants may be safe options, since they inhibit CYP3A more

weakly.35,36 Conversely, fexofenadine or loratadine, neither of which are

associated

with arrhythmias, could be prescribed, thus permitting more freedom in the

choice of an antidepressant. TABLE 2

Substrates, Inhibitors and Inducers of CYP3A

Substrates

Amitriptyline* (Elavil)

Benzodiazepines

Alprazolam (Xanax)

Triazolam (Halcion)

Midazolam (Versed)

Calcium blockers

Carbamazepine (Tegretol)

Cisapride (Propulsid)

Dexamethasone (Decadron)

Erythromycin

Ethinyl estradiol (Estraderm, Estrace)

Glyburide (Glynase, Micronase)

Imipramine* (Tofranil)

Ketoconazole (Nizoral)

Lovastatin (Mevacor)

Nefazodone (Serzone)

Terfenadine (Seldane)

Astemizole (Hismanal)

Verapamil (Calan, Isoptin)

Sertraline (Zoloft)

Testosterone

Theophylline*

Venlafaxine (Effexor)

Protease inhibitors

Ritonavir (Norvir)

Saquinavir (Invirase)

Indinavir (Crixivan)

Nelfinavir (Viracept)

Inhibitors

Antidepressants

Nefazodone > fluvoxamine (Luvox) > fluoxetine

(Prozac) > sertraline

Paroxetine (Paxil)

Venlafaxine

Azole antifungals

Ketoconazole (Nizoral) > itraconazole (Sporanox)

> fluconazole (Diflucan)

Cimetidine (Tagamet)†

Clarithromycin (Biaxin)

Diltiazem

Erythromycin

Protease inhibitors

Inducers

Carbamazepine

Dexamethasone

Phenobarbital

Phenytoin (Dilantin)

Rifampin (Rifadin, Rimactane)

 

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*--Other enzymes are involved.

†--Does not inhibit all CYP3A substrates; does not inhibit terfenadine

metabolism.

NOTE: Inhibitors will decrease metabolism of substrates and generally lead

to increased drug effect (unless the substrate is a prodrug). Inducers will

increase metabolism of substrates and generally lead to decreased drug effect

(unless the substrate is a prodrug).

Cisapride. Serious ventricular arrhythmias have been reported in patients

taking cisapride (Propulsid) and drugs that inhibit CYP3A, the isoform

responsible for metabolism of cisapride.37 Ketoconazole, fluconazole,

itraconazole,

metronidazole, erythromycin and clarithromycin have been associated with

cisapride-induced torsade de pointes.37 Concurrent use of cisapride with

fluoxetine, sertraline, fluvoxamine and nefazodone might be problematic because

of

CYP3A inhibition.38 Erythromycin, clarithromycin and ketoconazole

inhibit CYP3A, causing build-up of drugs metabolized by the same enzyme.

Terfenadine and cisapride are examples of drugs that can rise to cardiotoxic

levels.

 

Theophylline. Erythromycin39 and clarithromycin40 (but not azithromycin41)

decrease theophylline metabolism by inhibiting CYP3A. The interaction between

erythromycin and theophylline is most likely to occur in patients receiving

higher dosages of erythromycin and increases with the duration of therapy.

Inducers of CYP3A. Because of the resurgence of tuberculosis in the United

States, rifampin (Rifadin, Rimactane), an inducer of the CYP3A subfamily, is

being prescribed more widely than in previous years. Of particular clinical

relevance is the potential reduction of oral contraceptive efficacy by

rifampin, since estradiol levels can be reduced by rifampin-mediated CYP3A

induction.42 In addition to rifampin, potent glucocorticoids such as

dexamethasone

(Decadron) are also inducers of CYP3A, but lower-potency glucocorticoids, such

as

prednisolone, have minimal effect.43 TABLE 3

Substrates, Inhibitors and Inducers of CYP1A2

Substrates

Amitriptyline* (Elavil)

Clomipramine (Anafranil)*

Clozapine (Clozaril)*

Imipramine (Tofranil)*

Propranolol (Inderal)*

R-warfarin*

Theophylline*

Tacrine (Cognex)

Inhibitors

Fluvoxamine (Luvox)

Grapefruit juice

Quinolones

Ciprofloxacin (Cipro)

Enoxacin (Penetrex) > norfloxacin (Noroxin) >

ofloxacin (Floxin) > lomefloxacin (Maxaquin)

Inducers

Omeprazole (Prilosec)

Phenobarbital

Phenytoin (Dilantin)

Rifampin (Rifadin, Rimactane)

Smoking

Charcoal-broiled meat*

 

__

*--Other enzymes involved.

 

NOTE: Inhibitors will decrease metabolism of substrates and generally lead

to increased drug effect (unless the substrate is a prodrug). Inducers will

increase metabolism of substrates and generally lead to decreased drug effect

(unless the substrate is a prodrug).

CYP1A2

CYP1A2 can be induced by exposure to polycyclic aromatic hydrocarbons, such

as those found in charbroiled foods and cigarette smoke.44 This is the only

P450 isoform affected by tobacco. Cigarette smoking can result in an increase

of as much as threefold in CYP1A2 activity.44 Theophylline is metabolized in

part by CYP1A2,45 which explains why smokers require higher doses of

theophylline than nonsmokers. Table 3 lists the substrates, inhibitors and

inducers

of CYP1A2.

Quinolones. Certain quinolone antibiotics can inhibit theophylline

metabolism,46-48 although this effect is highly variable. The interaction

between

enoxacin (Penetrex) or ciprofloxacin (Cipro) and theophylline47 is most

significant in patients with plasma theophylline concentrations at the upper

end of

normal. Conversely, norfloxacin (Noroxin) and ofloxacin (Floxin) have little

effect on theophylline concentrations,46 and lomefloxacin (Maxaquin) does not

appear to alter the pharmacokinetics of theophylline.49 Since cimetidine is an

inhibitor of CYP1A2,17 additive inhibition of theophylline metabolism

occurs when cimetidine is combined with a fluoroquinolone.

CYP2E1

This isoform is inducible by ethanol and isoniazid and is responsible in

part for the metabolism of acetaminophen.50 The product of acetaminophen's

cytochrome P450 metabolism is a highly reactive intermediate that must be

detoxified by conjugation with glutathione.51 Patients with alcohol dependence

may

be at increased risk for acetaminophen hepatotoxicity because ethanol induction

of CYP2E1 increases formation of this reactive intermediate, and glutathione

concentrations are decreased in these patients.52 Cimetidine exhibits only

moderate affinity for this isoform and produces no significant inhibition of

the production of acetaminophen's toxic metabolite.17 Table 4 lists the

substrates, inhibitors and inducers of CYP2E1.

CYP2C9

S-Warfarin. Warfarin is produced as a racemic mixture of R-warfarin and

S-warfarin, but the predominance of pharmacologic activity resides in the

S-enantiomer.53 Most metabolism of S-warfarin is by means of CYP2C9,54 and

inhibi

tion of this isoform results in several clinically important drug interactions.

Fluconazole, metronidazole, miconazole and amiodarone are a few examples of

the many drugs that profoundly inhibit S-warfarin metabolism and produce

marked increases in prothrombin time measurements.55-58 Interestingly,

cimetidine,

a very weak inhibitor of CYP2C9,17 has been shown to have very little effect

on warfarin concentrations.59 The substrates, inhibitors and inducers of

CYP2C9 are listed in Table 5. TABLE 4

Substrates, Inhibitors and Inducers of CYP2E1

Substrates

Acetaminophen (Tylenol)

Ethanol

Inhibitors

Disulfiram (Antabuse)

Inducers

Ethanol

Isoniazid (Laniazid)

__

NOTE: Inhibitors will decrease metabolism of substrates and generally

lead to increased drug effect (unless the substrate is a prodrug). Inducers

will

increase metabolism of substrates and generally lead to decreased drug

effect (unless the substrate is a prodrug).

Phenytoin. Phenytoin is primarily metabolized via CYP2C9,60 although CYP2C19

may also play a small role.61 As stated above, cimetidine is a weak

inhibitor of CYP2C9. It is most likely to cause clinically significant

inhibition of

phenytoin metabolism at cimetidine dosages greater than 1,200 mg in patients

at the upper end of the phenytoin therapeutic range.62 In patients with

nonlinear metabolism of phenytoin at relatively low serum levels, the risk of

interaction with cimetidine is increased. However, it is difficult to identify

these patients in a clinical situation.

CYP2C19

Like CYP2D6, CYP2C19 has been shown to exhibit genetic polymorphism.63,64

This enzyme is completely absent in 3 percent of Caucasians and 20 percent of

Japanese. Drugs metabolized by this isoform include omeprazole (Prilosec),65

lansoprazole (Prevacid)66 and diazepam (Valium).67 However, clinical examples

of excessive or adverse drug effects in people who are CYP2C19-deficient are

lacking. Table 6 lists the substrates and inhibitors of CYP2C19.

TABLE 5

Substrates, Inhibitors and Inducers of CYP2C9

Substrates

Nonsteroidal anti-inflammatory drugs

Phenytoin (Dilantin)

S-warfarin

Torsemide (Demadex)

Inhibitors

Fluconazole (Diflucan)

Ketoconazole (Nizoral)

Metronidazole (Flagyl)

Itraconazole (Sporanox)

Ritonavir (Norvir)

Inducers

Rifampin (Rifadin, Rimactane)

__

NOTE: Inhibitors will decrease metabolism of substrates and generally

lead to increased drug effect (unless the substrate is a prodrug). Inducers

will

increase metabolism of substrates and generally lead to decreased drug

effect (unless the substrate is a prodrug). TABLE 6

Substrates and Inhibitors of CYP2C19

Substrates

Clomipramine (Anafranil)*

Diazepam (Valium)*

Imipramine (Tofranil)*

Omeprazole (Prilosec)

Propranolol (Inderal)*

Inhibitors

Fluoxetine (Prozac)

Sertraline (Zoloft)

Omeprazole

Ritonavir (Norvir)

__

 

*--Other enzymes involved also.

NOTE: Inhibitors will decrease metabolism of substrates and generally lead

to increased drug effect (unless the substrate is a prodrug). Inducers will

increase metabolism of substrates and generally lead to decreased drug effect

(unless the substrate is a prodrug).

Illustrative Case 2

A 47-year-old man recently diagnosed with HIV infection visited his

physician with flushing, dizziness and swelling of the feet and ankles. He had

been

taking sustained-release nifedipine for treatment of hypertension for about

three years. Approximately two weeks earlier, his physician had prescribed a

combination of lamivudine, zidovudine and the protease inhibitor ritonavir.

The HIV-1 protease inhibitors ritonavir, indinavir, saquinavir and

nelfinavir all inhibit the CYP3A subfamily of enzymes, thus increasing the

serum

levels of other drugs that are metabolized by this pathway, including

nifedipine.

It is likely that the addition of ritonavir to this patient's medical regimen

resulted in an increase in the serum level of nifedipine and the subsequent

symptoms of flushing and dizziness. Of the currently available protease

inhibitors, ritonavir, because of its ability to both inhibit and induce CYP450

enzymes, is associated with the most drug-drug interactions.68

Final Comment

Physicians who become familiar with the role of the various cytochrome P450

enzymes in drug metabolism can often predict the consequences of drug

interactions and explain patients' responses to medication regimens. Although

tests

for isoform expression are not widely available, it is conceivable that such

testing may become standard practice in the future, given the clinical

importance of isoform deficiencies. In the future, testing may help to identify

individuals at risk for drug interactions and adverse events.

 

__

The Authors

MELANIE JOHNS CUPP, PHARM.D.,

is a clinical assistant professor at West Virginia University School of

Pharmacy and a drug information specialist at West Virginia Drug Information

Center, both in Morgantown. She earned her pharmacy degree at West Virginia

University School of Pharmacy and completed a hospital pharmacy practice

residency

at West Virginia University Hospitals.

TIMOTHY S. TRACY, PH.D.,

is an assistant professor of clinical pharmacology in the Department of

Basic Pharmaceutical Sciences at the West Virginia University School of

Pharmacy.

He earned a Ph.D. in pharmacy from Purdue University, Lafayette, Ind., and

completed a postdoctoral fellowship in clinical pharmacology at the Indiana

University School of Medicine, Indianapolis.

Address correspondence to Melanie Johns Cupp, Pharm.D., West Virginia

University School of Pharmacy, 1124 HSN, P.O. Box 9550, Morgantown, WV

26506-9550.

Reprints are not available from the authors.

Richard W. Sloan, M.D., R.PH., coordinator of this series, is chairman and

residency program director of the Department of Family Medicine at York (Pa.)

Hospital and clinical associate professor in family and community medicine at

the Milton S. Hershey Medical Center, Pennsylvania State University,

Hershey, Pa.

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