Cytochrome P450 - New Nomenclature and Clinical Implications

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C L I N I C A L P H A R M A C O L O G Y

Cytochrome P450: New Nomenclatureand Clinical ImplicationsMELANIE JOHNS CUPP, PHARM.D., and TIMO THY S. TRACY, PH.D.West Virginia University School of Pharmacy, Morgantown, West Virginia

Many drug interactions are a result of inhibition or induction ofcytochrome P450enzymes (CYP450). The CYP 3A subfamily is involved in manyclinically significant ,drug interactions, includingthose involving nonsedating antihistamines and cisapride,that m ay resu lt in cardiac dysrhythmias. CYP3A4 and CYP1A 2 enzymes areinvolvedin drug interactions involving theophyUine. CYP2D 6 isresponsible for the metabolismof many psychotherapeutic agents. The protease inhibitors, which are used to treatpatients infected with the human immunodeficiency virus, are metabolized by theCYP450 enzymes andconsequently interact with a multitude ofother medications. By

understanding the unique functions andcharacteristics of these enzymes, physiciansmay better anticipate and manage drug interactions and may predict or explain anindividual's response to a particular therapeutic regimen.

Richard W. Sloan,M.D., R.PH.,coordinator of thisseries, is chairmanand residencyprogram directorof the Department ofFamily Medicineat York (Pa.)Hospital and clinicalassociate professor infamily and communitymedicine at the MiltonS. Hershey MedicalCenter, PennsylvaniaState U niversity, Her-shey, Pa .

The basic purpose of drug m etab-olism in the body is to makedrugs more water soluble andthus more readily excreted inthe urine or bile.'-^ One com-

mon way of metabolizing drugs involves thealteration of functional groups on the parent

molecule (e.g., oxidation) via the cytochromeP450 enzymes. These enzymes are most pre-dom inan t in the liver but can also be found inthe intestines, lungs and other organs.'*These cytochrome P450 enzymes are desig-nated by the letters "CYP" followed by an Ara-bic numeral, a letter and another Arabicnumeral (e.g., CYP2D6).^ Each enzyme istermed an isoform since each derives from adifferent gene. It should be noted, however,that structural similarity of enzymes cannotbe used to predict which isoforms will beresponsible for a drug's metabolism.

Drug interactions involving the cyto-chrome P450 isoforms generally result fromone of two processes, enzyme inhibition orenzyme indu ction. Enzyme inhibition usually

Until genetic tests for isoform expression become available, aphysidm can often antidpBte drug interactions in a patient by

. knowing-i^c-hniedications inhibitorinduce P450 enzymes.

involves competition with another drug forthe enzyme binding site. This process usuallybegins with the first dose of the inhibitor,*and onset and offset of inhibition correlatewith the half-lives of the drugs involved.'

Enzyme induction occurs when a drugstimulates the synthesis of more enzyme protein,' enhancing the enzyme's metabolizingcapacity. It is somew hat difficult to predict thetime course ofenzyme induction because sev-eral factors, including drug half-lives andenzyme turnover, determine the time courseof induction.

Illustrative Case 1

A 74-year-old woman with insulin-dependent (type 2) diabetes had been taking m etoprolol and warfarin for atrial fibrillation and

amitriptyline, 50 mg at bedtime, for diabeticneuropathy, for several years. On the dea th oher husban d, she presented w ith sym ptoms odepression, and paroxetine was added to hemedication regimen with the rationale thaparoxetine would cause fewer side effects thanan increase in the amitriptyline dosage. Thredays after the initiation of paroxetine therapythe woman was brought to the emergencydepartment by her daughter, who had foundher asleep at 11 a.m. On awakening, thepatient complained of dry mouth and dizzi

ness. The emergency department physician


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Cytochrome P450

die anadepres-ing deoendi, on

conccimitdnt medicst'oos.

noting that paroxetine had recently beenadded to the medication regimen, changedthe patient to fiuoxetine, which he thoughtwould be less sedating. Three days later, thepatient was still very sedated and dizzy, and

complained of difficulty urinating. She wasagain brought to the emergency department,where bladder catheterization yielded twoliters of dark urine. Her International N orma-lized Ratio (INR) was 4.0.

On discussion with a colleague, the emer-gency department physician learned that bothparoxetine and fiuoxetine can inhibit cyto-chrom e P450 enzymes (isoforms) responsiblefor the metabolism of the patient's othermed ications. This example illustrates the needto understand the cytochrome P450 isoformsresponsible for drug metabolism and theirinhibitors and inducers.

Cytochrome P450 IsoformsCYP2D6

CYP2D6 has been studied extensivelybecause it exhibits genetic polymorphism,meaning that distinct population differencesare apparent in its expression or activity.Approximately 7 to 10 percent of Caucasiansare poor m etabolizers of drugs metabolized by

CYP2D6."' Individuals with normal CYP2D6activity are termed extensive metabolizers.Ethnic differences are indicated in this geneticpolymorphism, since Asians and blacks areless likely than Caucasians to be poo r metabo -lizers."''^ Poor metabolizers are at risk fordrug accumulation and toxicity fi-om drugsmetabolized by this isoform. For example, onepatient who suffered cardiotoxicity induced bydesipramine (Norpramin) was found to be apoor metabolizer." Poor metabolizers ofCYP2D6 substrates are at risk for posturalhypotension and antipsychotic side effects

such as oversedation, because several antipsy-chotic agents are metabolized by CYP2D6.'''In a study of45 elderly patients (five of whomwere poor metabolizers) receiving per-phenazine , side effects increased fivefold n thepoor metabolizers compared with the exten-sive metabolizers.'^ Conversely, when forma-tion of an active metabolite is essential fordrug action, poor metabolizers of CYP2D6can exhibit less response to drug the rapy com-pared with extensive m etabolizers. Codeine is

0-demethylated to morphine by CYP2D6,which accounts at least partially for its anal-gesic effect."^ Thus, poor metabolizers mayhave less response to codeine than other per-sons. The substrates and inhibitors ofCYP2D6 are listed inTable 1.

Psychotherapeutic Agents. Many antidepres-sants are metabolized by CYP2D6, but othercytochrome P450 isoforms can also con tributeto their metabolism (Tables 1 through 6) . Theclinical importance of this "dual metabolism"will be illustrated later. With respect to drugsinhibiting CYP2D6, cimetidine (Tagamet), theselective serotonin reuptake inhibitors (SSRIs)and some tricyclic antidepressants function asinhibitors of this P450 isoform."-" Of theantidepressants, paroxetine (Paxil) appears tohave the greatest ability to inhibit the me tabo-lism of CYP2D6 substrates. This is followed byfiuoxetine (Prozac) and norfluoxetine; sertra-line (Zoloft) and desmethylsertraline; fiuvox-amine (Luvox), nefazodone (Serzone) andvenlafaxine (Effexor); clomipramine (Anaira-

nil), and amitriptyline (Elavil)." This rankingis based on in vitro data, however, and thechoice of an antidepressant should be basedon factors other than the propensity to inhibitCYP2D6. Although sertraline appears to beless likely than the other SSRIs to inhibitCYP2D6, inhibition may still occur at dosesgreater than 50mg. The clinical significance ofthe inhibition of tricyclics by SSRIs or cimeti-dine is subject to variation in enzyme activitybetween individuals, the degree to which thepatient metabolizes and co-ingestion of otherenzyme inhibitors.^"


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CYP3A

Inhibitors ofCYP3A.Members of the CYP3Asubfamily are the most abundant cytochromeenzymes in hum ans. They account for 30 per-cent of the cytochrome P450 enzymes in theliver^' and are also substantially expressed inthe intestines. Members of this subfamily areinvolved in many clinically important druginteractions.' Substrates, inhibitors and induc-ers of CYP3A are listed in Table 2.

Nonsedating Antihistamines.High plasmaconcentrations of terfenadine (Seldane) andastemizole (Hismanal) have been associatedwith torsade de pointes,a life-threatening car-diac arrhythmia characterized by altered car-diac repolarization an da prolonged QT inter-val. ^ Terfenadine is a prodrug that undergoescomplete first-pass metabolism to an activecarboxymetabolite. ' Itis therefore unusual todetect terfenadine in the plasma of patientswho take this drug at the recommendeddosage. Since it is terfenadine rather than its

active metabolite that is cardiotoxic, arrhyth-mias occur when a build-up of parent terfen-adine takes place. This may occur w hen azoleantifungal medications or macrolide antibi-otics are taken concomitantly. ^'^''To counter-act this problem, fexoferiadine (Allegra), theactive metabolite of terfenadine, is now mar-keted as a noncardiotox ic alternative to terfe-nadine. Like fexofenadine, loratadine (Clari-tin) does not appear to be cardiotoxic andthus is also a safe nonsedating antihistaminealternative.^^

Ketoconazole (Nizoral), itraconazoie (Spo-ranox) and fluconazole (Diflucan) inhibitCYP3A, although ketoconazole and itracona-zoie are more inhibiting than fluconazole.^*Based on in vitro and in vivo studies, keto-conazole and itraconazoie markedly inhibitmetabolism of terfenadine, causing changesin the QT interval."" At dosages of 200 mgdaily, fluconazole did no t result in accumula-tion of parent terfenadine or changes ih theQT interval.^" However, an interaction with

terfenadine and fluconazole coadministration

may occur in patients taking higher dosages offluconazole or in patients with risk factors forventricular arrhythmia. These two drugsshould be used together with caution.

In addition to the azole antifungal med-ications, the macrolide antibiotics can alsoinhibit terfenadine metabolism, resulting inthe development of torsade de pointes.Erythromycin and clarithromycin (Biaxin)have been shown to alter terfenadinemetabolism, but this does not appear tooccur with azithromycin (Zithromax).^'Thus, a patient who is taking terfenadineand needs macrolide antibiotic therapyshould be given azithromycin to avoid pos-sible cardiac consequences.

TABLE 1Substrates 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)

Eluphenazine (Prolixin)

Antipsychotics

Haloperidol

Perphenazine

Thioridazine

* O th er enzymes are also involved.

NOTE: Inhibitors will decrease metabolism of substrates and generally lead toincreased drug effect (unless the substrate is a prodrug). inducers will increasemetabolism of substrates and generally lead to decreased drug effect (unless

the substrate is a prodrug).


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Cytochrome P450

The SSRIs are 28 to 775 times less potent asinhibitors of terfenadine metabolism thanketoconazole.^ With respect to ability toinhibit CYP3A, the following order of theSSRIs is observed: nefazodone is greater thanfluvoxamine, and norfluoxetine is greater thanfluoxetine, which is greater than sertraline,desmethylsertraline,paroxetine and venlafax-ine.^' Several clinically important cardiacevents have been reported in patients receiving

fluoxetine or fluvoxamine with terfenadine orastemizole.^"'^^'^^The use of fluvoxamine ornefazodone with terfenadine or astemizole iscontraindicated, and the U.S. Food and DrugAdministration is currently considering requir-ing a contraindication against the use of otherSSRIs with the nonsedating antihistamines.'"The package insert for sertraline contains awarning against its use with terfenadine andastemizole.'"* In patients who need to take an

TABLE 2

Substrates, Inhibitors and tnduoers 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 (Zoloff)

Testosterone

Theophylline* '

Venlafaxine (Effexor)

Protease inhibitors

Ritonavir (Norvir)

Saquinavir (Invirase)

Indinavir (Crixivan)

Nelfinavir (Viracept)

Inhibitors

Anfidepressants

Nefazodone > fluvoxamine (Luvox) > fluoxetine

(Prozac) > sertraline

Paroxetine (Paxil)

Venlafaxine.

Azole antifungals

Ketoconazole (Nizoral) > itraconazoie (Sporanox)

> fluconazole (Diflucan)

Cimetidine (Tagamet)t

Clarithromycin (Biaxin) ,

Diltiazem

Erythromycin

Protease inhibitors

Inducers

Carbamazepine

Dexamethasone

Phenobarbital

Phenytoin (Dilantin)

Rifampin (Rifadin, Rimactane)

* Other enzymes are involved.

t Does not inhibit ail CYP3A substrates: does not inhibit terfenadine metabolism.

NOTE: Inhibitors vi/ill 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).


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antidepressant and a nonsedating antihista-mine concurrently, paroxetine, venlafaxine andtricyclic antidepressants may be safe options,since they inhibit CYP3A m.ore weakly.^^'^*^Conversely, fexofenadine or loratadine, neitherof which are associated with arrhythmias,could be prescribed, thus permitting morefreedom in the choice of an antidepressant.'

Cisapride. Serious ventricular arrhythmiashave been reported in patients taking cis-apride (Propulsid) and drugs that inhibit

CYP3A, the isoform responsible for metabo-lism of cisapride.^^ Ketoconazole, fluconazole.

TABLE 3Substrates, Inhibitorsand Inducers of CYIP1A2

_ JSubstrates

Amitriptyline* (Elavil)

Clomipramine (Ahafranil)*-

Clozapine (Clozaril)* .

Imipramine (Tofranil)*

Propranolol (Inderal)*

R-warfarin*

Theophyiline*

Tacrine (Cognex)

InhibitorsFluvoxamine (Luvox)

Grapefruit juice

Quinolones

Ciprofloxacin (Cipro)

Enoxacin (Penetrex) > norfloxacin (Noroxin) >ofloxacin (Floxin) > lomefloxacin (Maxaq uin)

Inducers

Omeprazole (Prilosec)

Phenobarbital

Phenytoin-(Dilantin)


Smoking

Charcoal-broiled meat*

*Other enzymes involved.

NOTE: Inhibitors willdecrease metabolism of sub-strates an d generally lead to increased drug effect(unless the su bstrate is a prodrug). Inducers wiilincrease metabolism of substrates and generallylead to decreased drug effect (unless the substrateis a prodrug).

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.

itraconazole, metronidazole, erythromycinand clarithromycin have been associated withcisapride-induced torsade de pointes.^^ Con-

current use of cisapride with fluoxetine, ser-traline, fluvoxamine and nefazodone m ight beproblematic because of CYP3A inhibition. "

Theophylline. Erythromycin'^ and clarith-romycin*" (but not azithromycin'") decreasetheophylline metabolismby inhibiting CYP3 A.The interaction between erythromycin andtheophylline is most likely to occur in patientsreceiving higher dosages of erythromycin andincreases with the du ration of therapy.

Inducers of CYP3A.Because of the resur-gence of tuberculosis in the United States,rifampin (Rifadin, Rimactane), an inducer ofthe CYP3A subfamily,is being prescribed m orewidely than in previous years. Of particularclinical relevance is the potential reduction oforal contraceptive efficacy by rifampin, sinceestradiol levels can be reduced by rifampin-mediated CYP3A induction.''^ In addition torifampin, potent glucocorticoids such as dex-amethasone (Decadron) are also inducers ofCYP3A, but lower-potency glucocorticoids,such as predniso lone, have minimal effect.''

CYP1A2

CYP1A2 can be induced by exposure topolycyclic aromatic hydrocarbons, such asthose found in charbroiled foods and cigarettesmoke.'*'' This is the only P450 isoform affect-ed by tobacco. Cigarette smoking can result inan increase ofas much as threefold in CYP1A2activity.'*'' Theophylline is metabolized in partby CYP1A2,'*^ which explains why smokersrequire higher doses of theophylline than n on -smokers. Table 3 lists the substrates, inhibitorsand inducers of CYP1A2.


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Cytochrome P450

Quinolones. Certain quinolone antibioticscan inhibit theophylline metabolism,'*'^'*''although this effect is highly variable.Theinteraction between enoxacin (Penetrex)orciprofloxacin (Cipro) and theophylline'*^ ismost significant in patients with plasma the-ophylline concentrationsat the upper end ofnormal. Conversely, norfloxacin (Noroxin)and ofloxacin (Floxin) have little effectontheophylline concentrations,'*''and lome-floxacin (Maxaquin) does not appear to alterthe pharmacokinetics of theophylline.'*' Sincecimetidine is an inhib itor of CYP1A2,' addi-tive inhibition of theophylline metabolismoccurs when cimetidineis combined withafluoroquinolone.

CYP2E1

This isoform is inducible by ethanolandisoniazid and is responsible in part for themetabolism of acetaminophen.^" The prod-uct of acetaminophen's cytochrome P450metabolism is a highly reactive intermediate

that must be detoxified by conjugation withglutathione.^' Patients with alcohol depen-dence may be at increased risk for aceta-minophen hepatotoxicity because ethanolinduction of CYP2E1 increases formation ofthis reactive intermediate,and glutathioneconcentrations are decreased in thesepatients.^^ Cimetidine exhibits only moder-

The AuthorsMELANIE JOHNS CUPP,PHARM.D.,is a clinical assistant professor at West Virginia Uni-versity School of Pharmacy and a drug information specialist at West Virginia DrugInformation Center, both in Morga ntow n. She earned her pharmacy degree at WestVirginia University School of Pharmacy and completed a hospital pharmacy practiceresidency at West Virginia University Hospitals.

TIMOTHY S. TRACY, PH.D.,is an assistant professor of clinical pharmacology in theDepartment of Basic Pharmaceutical Sciences at the West Virginia University SchoolofPharmacy. He earned a Ph.D. in pharmacy from Purdue University, Lafayette, Ind., andcompleted a postdoctoral fellowship in clinical pharmacology at the Indiana Universi-ty School of Medicine, indianapolis.

Address correspondence to Melanie Johns Cupp, Pharm.D., West Virginia UniversitySchool of Pharmacy 1124 HSN, P.O. Box 9550, Morgantown, VW 26506-9550.

Reprints are not available from the authors.

TABLE4

Substrates, Inhibitorsand Inducers of CYP2E1

Substrates

Acetaminophen (Tylenol)

Efhanol

Inhibitors

D isulfiram (Antabuse)

Inducers

Ethanol

Isoniazid (Laniazid)

NOTE: inhibitors will decrease metabolism of sub-strates and generally iead to increased drug effect(uniess the substrate is a prodrug). inducers wiilincrease metaboiism of substrates and generailylead to decreased drug effect (unless the substrateis a prodrug).

ate affinity for this isoform and producesnosignificant inhibition of the production ofacetaminophen's toxic metabolite.'^Table 4lists the sub strates, inhibitors an d ind ucers ofCYP2E1.

CYP2C9

S-Warfarin. Warfarin is produced as aracemic mixture of R-warfarin and S-war-farin, but the p redominance of pharmacolog-ic activity resides in the S-enantiomer.^^ Mostmetabolism of S-warfarin is by means ofCYP2C9,^'* and inhibition of this isoformresults in several clinically important druginteractions. Fluconazole, metronidazole,

micqnazole and amiodarone area few exam -ples of the many drugs that profoundly inhib-it S-warfarin metabolism and producemarked increasesin prothrombin time mea-surements.^^^'' Interestingly, cimetidine,avery weak inhibitor of CYP2C9,'^ has beenshown to have very little effect on warfarinconcentrations.^' The substrates, inhibitorsand inducers ofCYP2C9 are listed in Table 5.

Phenytoin. Phenytoin is primarily metab o-lized via CYP2C9,^'' although CYP2C19 mayalso play a small role.'"' As stated above, cime-

tidine is a weak inhibitor of CYP2C9. It is


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most likely to cause clinically significant inhi-bition of phenytoin metabolism at cimetidinedosages greater than 1,200 mg in patients atthe upper end of the phienytoin therapeuticrange.*^^ In patients with nonlinear metabo-lism of phenytoin at relatively low serum lev-els, the risk of interaction with cimetidine isincreased. However, it is difficult to identifythese patients in a clinical situation.

CYP2C19

Like CYP2D6, CYP2C19 has been shown toexhibit genetic polymorphism.'^-''''' This en-zyme is completely absent in 3 percent ofCaucasians and 20 percent of Japanese. Drugsmetabolized by this isoform include omepra-zole (Prilosec),''^ lansoprazole (Prevacid)''''and diazepam (Valium),,'^'' However, clinicalexamples of excessive or adverse drug effectsin people who are CYP2C19-deficient arelacking. Table 6 lists the substrates andinhibitors of CYP2C19.

Illustrative Case 2A 47-year-old man recently diagnosed with

HIV infection visited his physician with flush-ing, dizziness and swelling of the feet andankles. He had been taking sustained-releasenifedipine for treatment of hypertension forabout three years. Approximately two weeksearlier, his physician had prescribed a combi-nation of lamivudine, zidovudine and theprotease inhibitor ritonavir.

The HIV-1 protease inhibitors ritonavir,indinavir, saquinavir and nelfinavir all inhibitthe CYP3A subfamily of enzymes, thusincreasing the serum levels of other drugs thatare metabolized by this pathway, includingnifedipine. It is likely that the addition ofritonavir to this patient's medical regimenresulted in an increase in the serum level ofnifedipine and the subsequent symptoms offlushing and dizziness. Of the currently avail-able protease inhibitors, ritonavir, because ofits ability to both inhibit and induce CYP450enzymes, is associated v/ith the most drug-

drug interactions.'^*'

TABLE 5Substrates, Inhibitorsan d Inducers o f CYP2C9

Substrates

Nonsteroidal anti-inflammatory drugs

Phenytoin (Dilantin)S-warfarin

Torsemide (Demadex)

Inhibitors

Fluconazole (Diflucan)

Ketoconazole (Nizoral)

Metronidazole (Flagyl)

Itraconazole (Sporanox)

Ritonavir (Norvir)

Inducers


NOTE: Inhibitors will decrease metabolism of sub-strates and generally lead to increased drug effect(unless the substrate is a prodrug). Inducers willincrease metabolism of substrates and generallylead to decreased drug effect (unless the substrateis a prodrug).

TABLE 6Substrates and Inhibitorsof CYP2C19

Substrates

Clomipramine (Anafranil)*

Diazepam (Vaiium)*

Imipramine (Tofranil)*

Omeprazole (Priiosec)

Propranoioi (Inderal)*Inhibitors

Fiuoxetine (Prozac)

Sertraline (Zoloft)

Omeprazole

Ritonavir (Norvir)

*Other enzymes involved also.

NOTE: Inhibitors w ill decrease metabolism of sub-strates and generally lead to increased drug effect(unless the substrate is a prodrug). Inducers willincrease metabolism of substrates and generallylead to decreased drug effect (unless the substrate

is a prodrug).


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Cytochrome P450

Final Comment

Physicians who become familiar with therole of th e various cytochrome P450 enzymesin drug metabolism can often predict the con-sequences of drug interactions and explainpatients' responses to medication regimens.Although tests for isoform expression are notwidely available, it is conceivable that suchtesting may become standard practice in thefuture, given the clinical importance of iso-form deficiencies. In the future, testing may

help to identify individuals at risk for druginteractions and adverse events.

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Cytochrome P450 - New Nomenclature and Clinical Implications