cytp450 interacciones farmacologia cardiovascular -rev

8/11/2019 Cytp450 Interacciones Farmacologia Cardiovascular -Rev

1/9

Updates on Cytochrome P450-MediatedCardiovascular Drug Interactions

Judy W. M. Cheng, PharmD, MPH, FCCP, BCPS,1

William H. Frishman, MD,2

and Wilbert S. Aronow, MD 2*

Cytochrome P (CYP) 450 is a superfamily of hemoproteins that play an important role in themetabolism of steroid hormones, fatty acids, and many medications. Many agents used formanagement of cardiovascular diseases are substrates, inhibitors, or inducers of CYP450 enzymes.When two agents that are substrates, inhibitors, or inducers of CYP450 are administered together,drug interactions with signicant clinical consequences may occur. This review discusses CYP450-mediated cardiovascular drug interactions as well as noncardiovascular drug interactions thatproduced signicant cardiovascular side effects. The principles in predicting drug interactions arealso discussed.

Keywords: Cytochrome P 450, drug interactions, cardiovascular drugs

INTRODUCTION

Cytochrome P (CYP) 450 is a superfamily of hemo-proteins found in human liver and other tissues such asthe gastrointestinal tract that play an important role inthe metabolism of steroid hormones and fatty acids. 1

Its name was derived from its spectral absorbancemaximally produced near 450 nm when carbon mon-oxide binds to the enzyme at its reduced state. CYP450also plays a part in the metabolism of various drugsand exogenous chemicals. 1 Within the P450 superfam-ily, families are designated by Arabic numeral (eg,CYP3). Members of the same family have to have morethan 40% identical amino acid sequence. 2 If the aminoacid sequence is more than 55% identical, they will becategorized as a subfamily (eg, CYP3A). An Arabicnumeral is added to the subfamily to identify eachindividual enzyme (eg, CYP3A4). If the designation isprinted in italics, it represents the gene associated with

the enzyme (eg, CYP3A4). CYP1, CYP2, and CYP3 arethe three families responsible for most drug andcarcinogen metabolism. 1 The CYP1 family may alsoplay a role in carcinogenic activation, 1 whereas CYP2and CYP3 are characterized by their inducibility bydifferent medications such as phenobarbital 3,4 andtheir ability to metabolize a wide variety of drugs(Table 1). 1,5

Drugs that are metabolized by the same CYP450enzyme family, when administered concurrently, mayinteract and affect systemic clearance of each other. Thenature, extent, and clinical signicance of these inter-actions also depend on whether the interacting agentsare substrates, inducers, or inhibitors of the CYP450enzyme. Genetic polymorphism in the functionalexpression of some CYP450 enzymes, such as CYP2D6,also plays a signicant role in determining interpatientvariability in the degree of drug metabolism. Otherfactors such as age, nutrition, stress, hepatic disease,hormones, and other endogenous chemicals also playa role in determining the signicance of the druginteraction.

SUBSTRATES, INHIBITORS, ANDINDUCERS

A CYP450 substrate is an exogenous or endogenoussubstance metabolized by CYP450. Some drugs may

1 Arnold and Marie Schwartz College of Pharmacy and Sciences,Long Island University, Brooklyn, NY and the Mt. Sinai MedicalCenter, New York, NY; and 2Department of Medicine, New York Medical College/Westchester Medical Center, Valhalla, NY.*Address for correspondence: Cardiology Division, New York Medical College, Macy Pavilion, Room 138, Valhalla, NY 10595.E-mail: [email protected]

American Journal of Therapeutics 00, 000000 (2009)

10752765 2009 Lippincott Williams & Wilkins


2/9

be metabolized by more than one CYP450 enzyme andare considered substrates for multiple enzymes. Forexample, tricyclic antidepressants are metabolized byCYP2D6, CYP1A2, and CYP3A4.5 In this situation,when one of the enzymes is inhibited by another agent,a clinically signicant interaction may be less likely tooccur because of shared metabolism among enzymes.A CYP450 inhibitor is an exogenous or endogenoussubstance that will inhibit the activity of the CYP450enzymes but may not necessarily be metabolized bythe enzymes themselves (eg, cimetidine). Inhibitionoccurs as a result of competitive binding at the en-zyme s binding site, which prevents the enzyme frommetabolizing other agents. The onset and offset of enzyme inhibition by an individual inhibitor aredependent on the half-life of the inhibitor. For example,cimetidine ( with a half-life of approximately 2 hours

and inhibits CYP1A2) inhibits drug metabolism byCYP1A2 within 24 hoursof a single dose administration.But its inhibitory effect will also disappear within 24hours of drug discontinuation. On the other hand,amiodarones (with a half-life of 30 to 60 days andinhibits CYP2C9) inhibitory action may not take placefor months because of its long half-life, and itsinhibitory effect will also last for months after drugdiscontinuation. 6 Likewise, a CYP450 inducer is anagent that will increase the activity of CYP450 enzymes but also may not necessarily be metabolized by theenzymes themselves (eg, phenobarbital). Similarly toinhibitors, the onset of enzyme induction is dependenton the half-life of the inducer agent. In addition, thetime course of induction is also dependent on the timerequired for new enzyme production as well asa patients age and liver function. Table 2 lists some

Table 1 . Major drugs metabolized by cytochrome P450 enzymes. 1,51,5

CYP450 enzymes Substrate*

CYP1A2 Amitriptyline, caffeine, clomipramine, clozapine, cyclobenzaprine, desipramine, diazepam,estradiol, uvoxamine, haloperidol, imipramine, mexiletine , naproxen, olanzapine,ondansetron, acetaminophen, propranolol, theophylline, verapamil, warfarin ,zileuton, zolmitriptan

CYP2B6 Bupropion, cyclophosphamide, efavirenz, ifosfamide, methadoneCYP2C8 Paclitaxel, torsemide , repaglinideCYP2C9 Nonsteroidal anti-inammatory agents (diclofenac, ibuprofen, meloxicam, naproxen, piroxicam),

sulfonylurea (tolbutamide, gluburide, glipizide, glimerpiride, netaglinide), angiotensin II blockers(losartan , irbesartan ), amitriptyline, celecoxb, uoxetine, uvastatin, phenytoin, rosiglitazone,tamoxifen, torsemide , warfarin.

CYP2C18 Omeprazole, proguanil , propranolol , retinoic acid , S-mephenytoin, S-tetrahydrocannabinolCYP2C19 Proton pump inhibitors (lansoprazole, omeprazole, pantoprazole, rabeprazole), anti-epileptics

(diazepam, phenytoin, phenobarbital), amitriptyline, citalopram, clomipramine,cyclophosphamide, imipramine, indomethacin, nelnavir, primidone, progesterone,proguanil, propranolol , warfarin

CYP2D6 Antiarrhythmic agents (ecainide , mexiletine , propafenone ), antipsychotics (chlorpromazine,clozapine, haloperidol, resperidone), b -blockers , Fluoxetine, paroxetine, venlafaxine,metoclopramide, monoamine oxidase inhibitors, narcotics (codeine, hydrocodone, meperidine,methadone, morphine), ondesantron, tramadol, tricyclic antidepressants

CYP2E1 Anesthetics (eurane, halothane, isourane), acetaminophen, alcohol, theophyllineCYP3A3 Benzphetamine, erythromycin, cyclosporin, vinca alkaloidsCYP3A4, 5, 7 Clopidogrel (not 3A5, 3A7), macrolide antibiotics (clarithromycin, erythromycin (not 3A5),

telithromycin), antiarrhythmics (quinidine (not 3A5), amiodarone ), benzodiazepines(alprazolam, diazepam, midazolam, triazolam), immune modulators (cyclosporine, tacrolimus),antiretrovirals (indinavir, nelnavir, ritonavir, saquinavir), calcium channel blockers(amlodipine , diltiazem , felodipine , nifedipine , nisoldipine , nitrendipine , verapamil )HMGCoA reductase inhibitors (atorvastatin , lovastatin , simvastatin ), steroids(dexamethasone, estradiol, hydrocortisone, progesterone, testosterone), antipsychotics(aripiprazole, haloperidol, quetiapine, risperidol, ziprasodone), tricyclic antidepressants, cilostazol ,cocaine, caffeine, codeine, dapsone, dextromethorphan, eplerenone , fentanyl, methadone,natglinide, ondansetron, propranolol , salmeterol, sildenal, sirolimus, tamoxifen,trazadone, buspirone, zolpidem, zaleplon

CYP4A11 Leukotriene receptor antagonists

*Drugs in bold are cardiovascular agents.

American Journal of Therapeutics (2009) 00 (0)

2 Cheng et al


3/9

major inhibitors and inducers of different CYP450enzymes. 1,5

CLINICALLY SIGNIFICANT CYP450CARDIOVASCULAR DRUGINTERACTIONS

Angiotensin II receptor antagonists

Two of the angiotensin II receptor antagonists currentlyavailable on the market (losartan, irbesartan) aremetabolized by CYP2C9 (primarily) and CYP3A4 (toa minor extent). Although no signicant clinical druginteractions have been reported to date, signicantinhibition of these two enzymes by other agents canpotentially inhibit their metabolism, and thereforecareful monitoring of toxicity is required. It has beenreported that rifampin, by inducing CYP2C9 andCYP3A4 activities, decreases the half-life of losartan

and its metabolite by 50% in healthy volunteers.7

It hasalso beendemonstrated that when uconazole, a potentCYP2C9 inhibitor, was administered daily for 20 daysto 16 male subjects who received daily doses of losartan, it signicantly raised plasma concentrationsof losartan and inhibited formation of the activemetabolite. 8 These changes in plasma concentrations

of the active drugs and metabolites, however, did notproduce signicant changes in clinical response such asreduction in blood pressure.

Antiarrhythmic drugs

Quinidine is itself metabolized by the CYP3A4 enzyme but inhibits CYP 2D6. CYP3A4 interactions withquinidine that are well documented include those withcimetidine, phenytoin, phenobarbital, and rifampin. 912

Signicant interaction has also been reported betweenquinidine and erythromycin. 13 Erythromycin has beenreported to increase quinidine concentrations by 142%.Quinidine concentrations should be monitored andpatients assessed for signs of toxicity in these situations.

Amiodarone is also metabolized by the CYP3A4enzymes. Phenytoin, by inducing CYP3A4, has beenreported to enhance amiodarone metabolism anddecrease plasma concentrations by as much as 49%. 14

On the other hand, amiodarone inhibits CYP2C9, thus

inhibiting phenytoin metabolism, resulting in doublingplasma phenytoin levels. 15 When amiodarone is ad-ministered concurrently with warfarin therapy, pro-thrombin time may double in 3 to 4 days. 16 This is because warfarin is partially metabolized by CYP2C9,as with phenytoin. Similarly, quinidine also interactswith amiodarone, resulting in signicantly prolonged

Table 2 . Major inhibitors and substrates of different CYP450 enzymes. 1,5

CYP450 enzymes Inhibitors* Inducers*

CYP1A2 Amiodarone , cimetidine, ciprooxacin, clarithramycin,

erytrhomycin, oroquinolones, uvoxamine

Insulin, omeprazole, phenobarbital,

phenytoin, rifampin, smokingCYP2B6 Ticlopidine Phenobarbital, rifampinCYP2C8 Trimethoprim, glitazones, gembrozil , montelukast RifampinCYP2C9 Amiodarone , f enobrate , uconazole, uvastatin ,

uvozamine, isoniazid, lovastatin , phenybutazone,probenecid, seatrain, sulfamethoxazole, variconazole

Carbamazepine, phenobarbital,phenytoin, rifampin

CYP2C19 Chloramphenicol, cimetidine, uoxetine, uvoxamine,indomethacin, ketoconazole, lansoprazole, omeprazole,oxcarbamazepine, probenecid, ticlopidine , topiramate

Carbamazepine, prednisone, rifampin

CYP2D6 Amiodarone , buproprion, celecoxib, cimetidine,chlorpromazine, chlopheniramine, citalopram, cocaine,desipramine, diphenhydramine, doxepin, doxorubicin,escitalopram, uoxetin, uphenazine, haloperidol,metoclopramide, methadone, midodrine, paroxetin,

propafenone , quinidine , ranitidine, ritonavir,sertraline, ticlopidine

Carbamazepine, dexamethasone,phenobarbital, phenytoin, rifampin,ritonovir

CYP3A4, 5, 7 Amiodarone , cimetidine, clarithromycin, erythromycin,delaviridine, diltiazem , uconazole, uoxetin,uvoxamine, grapefruit juice, indinavir, itraconazole,ketoconazole, metronidazole, nefazodone, nelnavir,ritonavir, saquinavir, verapamil , voriconazole, zarlukast

Carbamazepine, corticosteroids,ethosuximide, phenobarbital,phenytoin, rifabutin, rifampin,glitazone

*Drugs in bold are cardiovascular agents.


CYP450 Cardiovascular Drug Interactions 3


4/9

QT intervals. Quinidine clearance is reduced byamiodarone, and plasma concentrations of quinidinemay increase by 32% when administered concurrently. 17

In addition, amiodarone may increase plasma concen-trations of hepatically metabolized beta-blockers andcalcium channel blockers. When the agents are admin-istered concomitantly, decreasing the doses of eachagent may be necessary. Antidepressants such asuvoxamine, uoxetine, sertraline, and nefazodonehave high CYP450 inhibitory potential and maydecrease amiodarone metabolism, thus increasingamiodarone plasma concentrations. 18

Antiplatelet drugs

Clopidogrel is a prodrug that requires in vivoconversion by CYP3A4 to an active metabolite (anunstable thiol compound) to exert its antiplateleteffect.1921 Because of this, if clopidogrel is adminis-tered with CYP3A4 inhibitors, the amount of active

metabolite produced may be decreased, thus dimin-ishing its antiplatelet effect. In a study evaluating theloading dose of clopidogrel in inhibiting plateletaggregation after coronary artery angioplasty, it wasobserved that the effectiveness of clopidogrel wasdiminished in patients who were taking atorvastatin. 22

The average platelet aggregation of patients receivingclopidogrel alone was 42% compared with thosewho received clopidogrel and atorvastatin (68%, P =0.03). Another study evaluated the ability of clopi-dogrel in inhibiting platelet aggregation in patientstaking either atorvastatin, a CYP3A4 inhibitor, orpravastatin, a non-CYP3A4 inhibitor. 23 Forty-four

patients undergoing coronary artery stent implanta-tion treated with clopidogrel demonstrated that thedegree of platelet aggregation inhibition achieved24 hours after clopidogrel administration was signif-icantly attenuated by atorvastatin as compared withthe controls (77% aggregation with atorvastatin vs.34% aggregation with placebo; P , 0.0001). In contrast,clopidogrel inhibited platelet aggregation in boththe control group and patients taking pravastatin(34% aggregation and 46% aggregation, respectively;P = NS).

Cilostazil is a phosphodiesterase inhibitor III in-dicated for management of intermittent claudication inpatients with peripheral arterial disease through itsantiplatelet activity. Cilostazil is metabolized by CYP1A2, 2D6, 3A, and 2C19. Its drug interaction prole hasnot been fully elucidated. A study demonstrated thatafter erythromycin coadministration, cilostazol maxi-mum plasma concentration increased signicantly by47%. The clinical signicance of such an interaction,however, is unknown. 24

Beta-adrenergic blockers

Pharmacokinetic proles of many lipophilic beta-adrenergic blockers such as propranolol are stronglyaffected by CY P450 inducers and inhibitors. 25 Forexample, rifampin causes a two- to threefold increase inpropranolol clearance, which lowers plasma propran-olol concentrations to subtherapeutic levels. 26 Quini-

dine inhibits CYP2D6 activity, thus inhibiting hepaticmetabolism of propranolol and raising its plasmaconcentrations. 26 Other clinically relevant drug inter-actions involving beta-blockers include cimetidine,which leads to additional reduction in heart rate andintraocular pressure when administered together withtimolol ophthalmic solution by inhibiting CYP2D6. 27,28

Calcium channel blockers

Most calcium channel blockers are metabolized exten-sively by CYP450 enzymes. When concurrent therapiesof potent CYP450 inhibitors are required, the patient

should be monitored for signs of toxicity (hypotension, bradycardia, or tachycardia) and the dosage of calciumchannel blocker decreased, if necessary. On the otherhand, when potent CYP450 inducers are administeredconcurrently with calcium channel blockers, the dosagemay have to be increased to achieve optimal thera-peutic effects.

Clinically signicant drug interactions caused byenzyme inhibition reported for calcium channel block-ers include that occurring with grapefruit juice, a potentCYP3A4 inhibitor. Grapefruit juice, 200 to 250 mL,when administered with felodipine, increased the areaunder the concentration time curve of felodipine by

185%. Similar results were demonstrated with nifed-ipine and verapamil but not with diltiazem. 29,30

Signicant drug interactions were also reported whenfelodipine (10 mg/day) was administered with oralerythromycin 250 mg twice daily. Patients developedushing, ankle and leg edema, as well as tachycardia. 31

Other reports also documented substantial peripheraledema or elevated felodipine serum concentrationswhen administered concurrently with itraconazole200 mg daily. This was also associated with statisticallysignicant changes in systolic and diastolic bloodpressures and heart rate. 32 Daily doses of cimetidine(8001200 mg) signicantly increased the mean totalarea under the plasma nifedipine concentration timecurve. Corresponding to this increase in the bio-availability of nifedipine caused by cimetidine, longerduration of changes in heart rate were observedin patients in the standing position. 33,34 These ndingsindicate that doses of nifedipine should be reduced by 50% when the drug is coadministered withcimetidine.


4 Cheng et al


5/9

Signicant drug interactions with calcium channel blockers caused by enzyme induction by other agentsinclude that with rifampin. Rifampin has been demon-strated to increase verapamil clearance by 32-fold. 35

Calcium channel blockers inhibit the metabolism of cyclosporine. 36 Diltiazem in doses as low as 10 mgincreased the bioavailability of cyclosporine andresulted in the need for a lower dose to maintainefcacy or avoid toxic effects. 37 Because cyclosporine isan expensive drug, the coprescribing of diltiazem andcyclosporine is a way of reducing the high costs of cyclosporine. 38 Similarly, the verapamil-inducedchangein cyclosporine pharmacokinetics allows the dose of cyclosporine to be reduced by one third to one half. 39

Verapamil signicantly increased mean peak serumconcentration and bioavailability of simvastatin. 40 Thisinteraction probably results from the inhibition of CYP3A4 or P-glycoprotein by verapamil. Although theclinical signicance of this nding is not clear, themanufacturer of simvastatin recommends to avoid

concurrent use of simvastatin and verapamil, and if thetwo agents must be used together, the dose of simvastatin be kept at a maximum of 20 mg. 41 Onemeta-analysis suggested that, overall, calcium channel blockers do not increase the risk of myopathy whenused concomitantly with simvastatin. 42

Diltiazem inhibits the metabolism of triazolam,probably by inhibiting the activity of CYP3A. 43 Whenpatients using diltiazem were anesthetized with largedoses of midazolam, a signicant delay in trachealextubation was attributed to reduced metabolism of these anesthetics secondary to inhibition of CYP3A bydiltiazem. 44 Similarly, diltiazem increased plasma

levels of methylprednisolone, which enhanced sup-pression of morning plasma cortisol levels. This ndingsuggests that care should be taken when methylpred-nisolone is coadministered with diltiazem for a pro-longed period of time. 45

Diuretics

Torsemide and eplerenone are two diuretics that aremetabolized by the CYP450 system (CPY2C4 andCYP3A4, respectively). A clinically signicant druginteraction of torsemide involving the CYP450 systemhas not been reported. Eplerenone is metabolizedprimarily by CYP3A4. A potent inhibitor of CYP3A4such as ketoconazole increased serum concentra-tion of eplerenone by vefold, whereas less potentCYP3A4 inhibitors such as erythromycin and vera-pamil increased serum concentration of eplerenone bythreefold. The administration of grapefruit juice witheplerenone was reported to increase serum eplerenoneconcentration by 25%. 46

3-hydroxy-3-methylglutaryl coenzyme a reductaseinhibitors

Three of the six 3-hydroxy-3-methylglutaryl coenzymeA (HMG-CoA) reductase inhibitors marketed in theUnited States are metabolized primarily by CYP3A4(atorvastatin, lovastatin, simvastatin). Dose-relatedtoxic effects on skeletal muscle are well documented

with HMG-CoA reductase inhibitors.47

Risk of de-veloping rhabdomyolysis increases as this class of drugis used in combination with other CYP3A4 inhibitoragents that compete with CYP3A4 metabolism (eg,cyclosporin, gembrozil, niacin, erythromycin). 48,49 Asmentioned in the previous section on calcium channel blockers, the manufacturer of simvastatin has madeseveral recommendations of daily maximum doses of simvastatin use when it is administered concurrentlywith several CYP3A4 inhibitors. 41 When administeredconcurrently with verapamil or amiodarone, the max-imum dosage of simvastatin used should not exceed20 mg per day to minimize the risk of myopathy. Whenadministered with cyclosporin, danazol, and gembrozil, the maximum daily dose of simvastatin usageshould not exceed 10 mg.

Bleeding or prolonged prothrombin time wasreported in several patients taking HMG-CoA reduc-tase inhibitor (those metabolized by CYP3A4) concomi-tantly with warfarin. 50 Fluvastatin and pravastatin, onthe other hand, have not been reported to interact withwarfarin.

Warfarin

Warfarin has an extensive drug interaction prole.

R-warfarin is a substrate of CYP3A4. Therefore, anymedications that are inducers or inhibitors of CYP3A4will interact with R-warfarin pharmacokinetically.Fluconazole, itraconazole, and ketoconazole have beenreported to increase the anticoagulant effects of warfarin by two- to three fold. 5153 Numerous reportsdescribe the enhancement of the hypoprothrombine-mic effects (up to 2-fold) of warfarin when given incombination with erythromycin and clarithromy-cin.54,55 Azithromycin has not been reported to havesuch an interaction. The clinical relevance of anywarfarin interactions depends on many other patientfactors including age, rates of warfarin clearance, andother concurrent drug therapy.

Omeprazole, a proton pump inhibitor, inhibits themetabolism of R-warfarin through inhibition of CY-P3A4 enzyme. The effects appear after omeprazole has been administered for a few days, and it appears to bedose related. This effect does not abate until severaldays after discontinuation of omeprazole. 56 Carefuldrug monitoring is therefore required.




6/9

CLINICALLY SIGNIFICANT CYP450NONCARDIOVASCULAR DRUGINTERACTIONS THAT PRODUCECARDIOVASCULAR SIDE EFFECTS

Antidepressants and antipsychotics

Certain selective serotonin reuptake inhibitors (SSRI)are substrates of CYP450 enzymes and potent inhib-itors of CYP2D6 (eg, uoxetine, nefazadone, parox-etine, sertraline). Antipsychotics, especially the newergeneration atypical antipsychotics, are substrates of CYP450 enzymes but neither inhibit nor induce theCYP450 enzymes. Coadministration of SSRI withtricyclic antidepressants and antiarrhythmics have been reported to increase the risk of developingTorsades de Pointes. 57,58 Several studies have docu-mented that uvoxamine, a new SSRI, may elevateplasma levels of olanzapine by approximately two

times, presumably through inhibition of CYP1A2,with possible occurrence of unwanted effects. Inparticular, in eight patients stabilized on olanzapinetherapy (1020 mg/day), the addition of uvoxamine(100 mg/day) for 8 weeks increased plasma olanzapinelevels by approximately 80%, which increased theincidence of sedation, orthostatic hypotension, tachy-cardia, and elevation of transaminase. 59

Antihistamines

Both terfenidine and aztemizole are two rst-generationnonsedating antihistamines that have been removedfrom the market because of their serious cardiovascular

drug interaction. Terfenidine and aztemizole aresubstrates of CYP3A4. Terfenidine was rst reportedto cause QT interval prolongation and Torsades dePointes when coadministered with ketoconazole in1990.60 A prospective study of six healthy volunteersgiven the combination were noted to have increasedterfenidine plasma concentrations and QT prolon-gation. 61 Such interaction is observed because of ketoconazoles inhibitory activity on CYP3A4 enzyme,which is responsible for metabolizing terfenidine. Thisleads to increased serum concentration of the parentcompound, terfenidine, which is arrhythmogenic.Other antifungal agents such as itraconazole anduconazole have less inhibitory effect on CYP3A4. 62Therefore, in dosages used clinically, the incidence of arrhythmia is low. 63 Astemizole undergoes extensiverst-pass metabolism to form active metabolites, andsimilar to terfenidine, the parent compound is also thecardiotoxic entity. Therefore, in many circumstances,drug interactions of terfenidine have been extrapolatedto astemizole. 64

Erythromycin is another inhibitor of CYP3A4enzyme and in itself can also cause QT prolongation. 64

Therefore, when coadministered with terfenidine oraztemizole, it may increase the risk of arrhythmia. 65

This effect was also reported with clarithromycin butnot with azithromycin. 66

Because the accumulations of terfenadine andaztemizole can lead to prolongation of QT intervalsand devastating arrhythmias, coadministration of theseantihistamines with other agents that are also capableof prolonging QT will, through a pharmacodynamicinteraction, increase the risk of developing Torsades dePointes. Agents that are known to prolong QT intervalsare listed in Table 3. 67

Antimicrobials and antifungals

Macrolides (except azithromycin) are substrates andinhibitors of CYP3A4. Coadministration of CYP3Ainhibitors (antifungal agents, diltiazem, verapamil, andtroleandomycin) with erythromycin has been associ-

ated with a doubling of the risk of sudden cardiac deathcaused by increased concentrations of erythromycin. 68

Ketoconazole, itraconazole, uconazole, and vorico-nazole have been shown to prolong the QT interval andto be associated with Torsades, with the majority of reports of Torsades stemming from CYP450 involvingdrug interactions and relating to ketoconazole anditraconazole. 6973 In addition, allelic polymorphisms of CYP2C19 have demonstrated the greatest impact onvoriconazole clearance, resulting in either poor orextensive metabolism of this drug and leading someto suggest the need for therapeutic drug monitoring. 74

To date, no postmarketing database evaluations charac-

terizing azole-associated Torsades have been published.Cisapride

Cisapride was rst observed in a review of recordsof more than 13,000 patients to cause tachycardia,

Table 3 . Pharmacologic agents capable of prolongingQT intervals. 41

AntiarrhythmicsAntipsychoticsChloroquinCisaprideDroperidolTricyclic antidepressantsFluconazoleItraconazoleKetoconazoleMacrolides (erythromycin, clarithomycin)MethadonePentamadine


6 Cheng et al


7/9

palpitations, and extrasystoles. 75 Postulations of thecause of tachycardia include activation of serotonin-4receptors on the myocardium and prolonged atrioven-tricular conduction because of its structural similarity toprocainamide. The rst report of arrhythmia druginteraction was reported between cisapride and eryth-romycin. The patient developed prolonged QT intervalwith progression to Torsades. 76 Since then, JanssenPharmaceutical, who markets cisapride, continues toreceive numerous reports of Torsades. More than 50%of these patients were concomitantly receiving othermedications that may prolong QT intervals. 77 Themechanism of these interactions is believed to becompetitive binding and inhibition of CYP3A4 enzyme by cisapride. In 2000, Janssen Pharmaceutical decidedto stop marketing Cisapride in the United States butcontinued to make the drug available to those patientswhom their physicians still considered to receive benets from cisapride that outweighed its risks. 78

Grapefruit juice

Grapefruit juice is a potent inhibitor of gut wallCYP3A4, which is important in metabolism of alldihydropyridines, HMG-CoA reductase inhibitors,cisapride, midazolam, and cyclosporin. It is nowknown that grapefruit juice on average increasesfelodipine area under the curve by 240% and increasesnisoldipine peak plasma concentration by vefold. 79,80

In addition to CYP3A4, grapefruit juice has alsodemonstrated to signicantly inhibit CYP1A2. 80 Thiswill be of particular importance in patients takingpropafenone and warfarin.

MethadoneRecent studies and case series have associated the useof methadone with development of prolonged QTintervals and Torsades. 81 Methadone is metabolized byCYP3A4 and to a lesser extent CYP2D6. Therefore,coadministration of methadone with agents that inhibitCYP3A4 and CYP2D6 may increase the risk of Torsades. In a case control study examining 40 patientswith reported methadone-induced Torsades dePointes, the concurrent use of agents that inhibitCYP3A4 increase the risk of Torsades by 55%. 82 Inone case series, therapy with nelnavir, a potent

inhibitor of CYP3A4, when administered with meth-adone, caused torsade de pointes. 83

CONCLUSION

Numerous cardiovascular agents are substrates, inhib-itors, or inducers of CYP450 enzymes. 84 The improvedunderstanding of the CYP450 system, their substrates,

inhibitors, and inducers allow us to predict potentialdrug interactions. This review discusses the generalprinciples of occurrence of these interactions withselected published signicant examples. Continuedin vivo drug interaction studies and reporting by clini-cians are necessary to establish the clinical signicanceof these interactions and will help to prevent andmanage these drug interactions.

REFERENCES

1. Gonzalez FJ. Molecular genetics of the P-450 superfamily.Pharmac Ther. 1990;45:138.

2. Slaughter RL, Edwards DJ. Recent advances: the cyto-chrome P450 enzymes. Ann Pharmacother. 1995;29:619624.

3. Guengerich FP, Dannan GA, Wright ST, et al. Puricationand characterization of liver microsomal cytochromeP450: electrophoretic, spectral, catalytic and immuno-chemical properties and inducibility of eight isozymes

isolated from rats treated with phenobarbital orB-naphthoavone. Biochemistry. 1982;21:60196030.4. Waxman DJ, Walsh C. Phenobarbital-induced rat liver

cytochrome P-450-purication and characterization of two closely related isozymic forms. J Biol Chem. 1982;2257:1044610457.

5. P450 tables. Available at: http://medicine.iupui.edu/ockhart/table.htm Accessed March 25, 2007.

6. Heimark LD, Wienkers L, Dunze K, et al. The mechanismof the interaction between amiodarone and warfarin inhumans. Clin Pharmacol Ther. 1992;51:398407.

7. Williamson KM, Patterson JH, McQueen RH, et al. Effectsof erythromycin or rifampin on losartan pharmacokinet-ics in healthy volunteers. Clin Pharmacol Ther. 1998;63:

316323.8. Kazierad DJ, Martin DE, Blum RA, et al. Effect of uconazole on the pharmacokinetics of eprosartan andlosartan in healthy male volunteers. Clin Pharmacol Ther.1997;62:417425.

9. Slaughter RL, Edwards DJ. Recent advances: the cyto-chrome P450 enzymes. Ann Pharmacother. 1995;29:619624.

10. Shinn AF. Clinical relevance of cimetidine drug inter-actions. Drug Saf . 1992;7;24567.

11. Levy RH. Cytochrome P450 isoenzyme and antiepilepticdrug interactions. Epilepsia. 1995;36(Suppl 5):S8S13.

12. Venkatesan K. Pharmacokinetic drug interactions withrifampin. Clin Pharmacokinet. 1992;22:4765.

13. Spinler S, Cheng JWM, Kindwall KE, et al. Possible

inhibition of hepatic metabolism of quinidine by eryth-romycin. Clin Pharmacol Ther. 1995;57:8994.14. Nolan PE Jr, Marcus FL, Karol MD, et al. Effect of

phenytoin on the clinical pharmacokinetics of amiodar-one. J Clin Pharmacol. 1990;30:11121119.

15. Gore JM, Haffajee CI, Alpert JS. Interaction of amiodaroneand diphenylhydantoin. Am J Cardiol. 1984;54:1145.

16. Marcus FI. Drug interactions with amiodarone. Am Heart J .1983;106:924930.




8/9

17. Saal AK, Werner JA, Greene HL, et al. Effect of amiodarone on serum quinidine and procainamide levels. Am J Cardiol. 1984;53:12641267.

18. DeVane CL, Gill HS, Markowitz JS, et al. Awareness of potential drug interactions may aid avoidance. Ther Drug Monit. 1997;19:366367.

19. Savi P, Pereillo JM, Uzabiaga MF, et al. Identication and biological activity of the active metabolite of clopidogrel.

Throm. Haemost. 2000;84:891896.20. Hasegawa M, Sugidachi A, Ogawa T, et al. Stereoselectiveinhibition of human platelet aggregation by R-138727,the active metabolite of CS-747 (prasugrel, LY640315),a novel P2Y12 receptor inhibitor. Thromb Haemost. 2005;94:593598.

21. Kazui M, Ishizuka T, Yamamura N, et al. Mechanism of production of pharmacologically active metabolites of CS-747, a new pro-drug ADP-receptor antagonist. Thromb Haemost. 2001;12(Suppl):P1916.

22. Lau C, L. Waskell LA, Carville D, et al. The antiplateletactivity of clopidogrel is inhibited by atorvastatin but not by pravastatin. Circulation. 2000;102:2086.

23. Lau C, Waskell LA, Watkins PB, et al. Atorvastatinreduces the ability of clopidogrel to inhibit plateletaggregation: a new drugdrug interaction. Circulation.2003;107:3237.

24. Suri A, Forbes WP, Bramer SL. Effects of CYP3Ainhibition on the metabolism of cilostazil. Clin Pharma-cokinet. 1999;37(Suppl 2):6168.

25. Wood AJ. Drug interactions in hypertension. Hyperten-sion. 1988;11:II-1II-3.

26. Herman RJ, Nakamura K, Wilkinson GR, et al. Inductionof propranolol metabolism by rifampicin. Br J ClinPharmacol. 1983;16:565569.

27. Ishii Y, Nakamura K, Tsutsumi K, et al. Drug inter-action between cimetidine and timolol ophthalmicsolution: effect on heart rate and intraocular pressure inhealthy Japanese volunteers. J Clin Pharmacol. 2000;40:193199.

28. Edeki TI, He H, Wood AJ. Pharmacogenetic explanationfor excessive beta-blockade following timolol eye drops:potential for oral-ophthalmic drug interaction. JAMA.1995;274:16111613.

29. Fuhr U, Dummert AL. The fate of naringin in humans:a key to grapefruit juice-drug interactions. Clin PharmacolTher. 1995;58:364373.

30. Abramowicz M, ed. Grapefruit juice interactions withdrugs. Med Lett. 1995;37:6364.

31. Nordine LH. Erythromycin-felodipine interaction [Let-ter]. Drug Intell Clin Pharm. 1991;25:10071008.

32. Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazolegreatly increases plasma concentrations and effects of felodipine. Clin Pharmacol Ther. 1997;61:410415.

33. Smith SR, Kendall MJ, Lobo J, et al. Ranitidine andcimetidine drug interactions with single dose and steady-state nifedipine administration. Br J Clin Pharmacol. 1987;23:311315.

34. Schwartz JB, Upton RA, LinET, et al. Effect of cimetidine orranitidine administration on nifedipine pharmacokinetics

and pharmacodynamics. Clin Pharmacol Ther. 1988;43:673680.

35. Fromm MF, Busse D, Kroemer HK, et al. Differentialinduction of prehepatic and hepatic metabolism of verapamil by rifampin. Hepatology. 1996;24:796801.

36. Chiu SH. The use of in vitro metabolism studies in theunderstanding of new drugs. J Pharmacol Toxicol Methods.1993;29:7783.

37. Jones DR, Gorski JC, Hamman MA, et al. Diltiazeminhibition of cytochrome P-450 3A activity is due tometabolite intermediate complex formation. J PharmacolExp Ther. 1999;290:11161125.

38. Jones TE, Morris RG, Mathew TH. Diltiazem-cyclosporinpharmacokinetic interaction: dose-response relationship.Br J Clin Pharmacol. 1997;44:499504.

39. Campana C, Regazzi MB, Buggia I, et al. Clinicallysignicant drug interactions with cyclosporin: an update.Clin Pharmacokinet. 1996;30:141179.

40. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin andverapamil considerably increase serum simvastatin andsimvastatin acid concentrations. Clin Pharmacol Ther.1998;64:177182.

41. Zocor prescribing information. Available at: http://www.zocor.com/zocor/shared/documents/english/pi.pdf.Accessed April 24, 2007.

42. Gruer PJ, Vega JM, Mercuri MF, et al. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol. 1999;84:811815.

43. Varhe A, Olkkola KT, Neuvonen PJ. Diltiazem enhancesthe effects of triazolam by inhibiting its metabolism. ClinPharmacol Ther. 1996;59:369375.

44. Ahonen J, Olkkola KT, Salmenpera M, et al. Effect of diltiazem on midazolam and alfentanil disposition inpatients undergoing coronary artery bypass grafting. Anesthesiology. 1996;85:12461252.

45. Varis T, Backman JT, Kivisto KT, et al. Diltiazem andmibefradil increase the plasma concentrations and greatlyenhance the adrenal-suppressant effect of oral methyl-prednisolone. Clin Pharmacol Ther. 2000;67:215221.

46. Cook CS, Berry LM. Burton E. Prediction of in vivo druginteractions with eplerenone in man from in vitrometabolic inhibition data. Xenobiotica. 2004;34:215228.

47. Bradford RH, Shear CL, Chremos AN, et al. Expandedclinical evaluation of lovastatin (EXCEL) study results.1. Efcacy in modifying plasma lipoproteins andadverse event prole in modifying plasma lipoproteinsand adverse event prole in 8245 patients withmoderate hypercholesterolemia. Arch Intern Med.1991;151:4349.

48. Illingworth DR, Tobert JA. A review of clinical trialscomparing HMG-CoA reductase inhibitors. Clin Ther.1994;16:366385.

49. Ayanian JZ, Ruchs CS, Stone RM. Lovastatin andrhabdomyolysis [Letter]. Ann Intern Med. 1988;109:682683.

50. Garnett WR. Interactions with hydroxymethylglutaryl-coenzyme A reductase inhibitor. Am J Health Syst Pharm.1995;52:16391645.


8 Cheng et al


9/9

51. Kunze KL, Wienkers LC, Thummel KE, et al.Warfarin-uconazole. 1. Inhibition of human cytochromeP450-dependent metabolism of warfarin by uconazole:in vitro studies. Drug Metab Dispos. 1996;24:422428.

52. Black DJ, Kunze KL, Wienkers LC, et al. Warfarin-uconazole. II. A metabolically based drug interaction:in vitro studies. Drug Metab Dispos. 1996;24:422428.

53. Gillum JG, Isreal DS, Polk RE. Pharmacokinetic drug

interactions with antimicrobialagents. Clin Pharmacokinet.1993;25:450482.54. Oberg KC. Delayed elevation of international normalized

ratio with concurrent clarithromycin and warfarintherapy. Pharmacotherapy. 1998;18:386391.

55. Gugler R, Jensen JC. Omeprazole inhibits oxidative drugmetabolism. Studies with diazepam and phenytoinin vivo and 7-ethoxycoumarin in vitro. Gastroenterolog.y1985;89:12351241.

56. Nemeroff CB, DeVane L, Pollock BG. Newer antidepres-sants and the cytochrome P450 system. Am J Psychiatry.1996;153:311320.

57. Brosen K. Are pharmacokinetic drug interactions withSSRIs an issue? Int Clin Psychopharmaco.l 1996;11(Suppl 1):

2327.58. Monahan BP, Ferguson CL, Killeavy ES, et al. Torsades depointes occurring in association with terfenidine use. JAMA. 1990;264:27882790.

59. Hiemke C, Avi P, Jabarin M, et al. Fluvoxamineaugmentation of olanzapine in chronic schizophrenia:pharmacokinetic interactions and clinical effects. J ClinPsychopharmacol. 2002;22:502506.

60. Honig PK, Woosley RL, Zamani K, et al. Terfenadine-ketoconazole interaction pharmacokinetic and electrocar-diographic consequences. JAMA. 1993;269:15131518.

61. Kivisto KT, Neuvonen PJ, Klotz U. Inhibition of terfenidine metabolism: pharmacokinetic and pharmaco-dynamic consequences. Clin Pharmacokinet. 1994;7:15.

62. Gillum JG, Isreal DS, Polk RE. Pharmacokinetic druginteractions with antimicrobialagents. Clin Pharmacokinet.1993;25:450482.

63. Oberg K, Bauman JL. QT interval prolongation andTorsades de pointes due to erythromycin lactobionate.Pharmacotherapy. 1995;15:687692.

64. Honig PK, Woosley RL, Zamani K, et al. Changes in thepharmacokinetics and electrocardiographic pharmacody-namics of terfenidine with concomitant administration of erythromycin. Clin Pharmacol Ther. 1992;52:213218.

65. Amsden GW. Macrolides versus azalides: a drug inter-action update. Ann Pharmacother. 1995;29:906917.

66. Inman W, Kubota K. Tachycardia during cisapridetreatment. BMJ . 1992;305:748749.

67. Arizona Center for Education and Research on Thera-peutics. Drugs with risk of Torsades de Pointes. Availableat: http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm. Accessed March 25, 2007.

68. Ray WA, Murray KT, Meredith S, et al. Oral erythromycinand the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:10891096.

69. Dorsey ST, Biblo LA. Prolonged QT interval and torsadesde pointes caused by the combination of uconazole andamitriptyline. Am J Emerg Med. 2000;18:227229.

70. Hoover CA, Carmichael JK, Nolan PE Jr, et al. Cardiacarrest associated with combination cisapride and itraco-

nazole therapy. J Cardiovasc Pharmacol Ther. 1996;1:255258.71. Khazan M, Mathis AS. Probable case of torsades depointes induced by uconazole. Pharmacotherapy. 2002;22:16321637.

72. Pohjola-Sintonen S, Viitasalo M, Toivonen L, et al.Itraconazole prevents terfenadine metabolism andincreases risk of torsades de pointes ventricular tachy-cardia. Eur J Clin Pharmacol. 1993;45:191193.

73. Zimmermann M, Duruz H, Guinand O, et al. Torsades depointes after treatment with terfenadine and ketocona-zole. Eur Heart J . 1992;13:10021003.

74. Smith J, Safdar N, Knasinski V, et al. Voriconazoletherapeutic drug monitoring. Antimicrob Agents Chemo-ther. 2006;50:15701572.

75. Bran S, Murray W, Hirsch IB, et al. Long QT syndromeduring high dose cisapride. Arch Intern Med. 1995;155:765768.

76. Wysowski DK, Bacsanyi J. Cisapride and fatal arrhyth-mia. N Engl J Med. 1996;335:290291.

77. Zechnich AD, Hedges JR, Eiselt-Proteau D, et al. Possibleinteractions with terfenidine or astemizole. West J Med.1994;160:321325.

78. Janssen Pharmaceutica stops marking Cisapride in theUS. Available at: http://www.fda.gov/bbs/topics/ANSWERS/ANS01007.html. Accessed March 29, 2007.

79. Flockhart DA. Drug interactions, cardiac toxicity, andterfenadine: from bench to clinic? J Clin Psychopharmacol.1996;16:101103.

80. Merkel U, Sigusch H, Hoffman A. Grapefruit juiceinhibits 7-hydroxylation of coumarin in healthy volun-teers. Eur J Clin Pharmacol. 1994;46:175177.

81 Pearson EC, Woosley RL. QT prolongation and torsadesde pointes among methadone users: reports to the FDAspontaneous reporting system. Pharmacoepidemiol DrugSaf . 2005;14:747753.

82. Krantz MJ, Lewkowiez L, Hays H, et al. Torsade depointes associated with very high dose methadone. Ann Intern Med. 2002;137:501504.

83. Justo D, Gal-Oz A, Paran Y, et al. Methadone associatedTorsades de Pointes (polymorphic ventricular tachycardia)in opioid-dependent patients. Addiction. 2006;101:13331338.

84. Opie LH. Cardiovascular drug interactions. In: FrishmanWH, Sonnenblick EH, Sica DA, eds. CardiovascularPharmacotherapeutics, ed 2. New York: McGraw Hill,2003: 875891.



cytp450 interacciones farmacologia cardiovascular -rev

Documents