Updates on Cytochrome P450-Mediated

Cardiovascular 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 the
metabolism of steroid hormones, fatty acids, and many medications. Many agents used for
management 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 that
produced signicant cardiovascular side effects. The principles in predicting drug interactions are
also 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 as
the gastrointestinal tract that play an important role in
the metabolism of steroid hormones and fatty acids.
1
Its name was derived from its spectral absorbance
maximally produced near 450 nm when carbon mon-
oxide binds to the enzyme at its reduced state. CYP450
also plays a part in the metabolism of various drugs
and exogenous chemicals.
1
Within the P450 superfam-
ily, families are designated by Arabic numeral (eg,
CYP3). Members of the same family have to have more
than 40% identical amino acid sequence.
2
If the amino
acid sequence is more than 55% identical, they will be
categorized as a subfamily (eg, CYP3A). An Arabic
numeral is added to the subfamily to identify each
individual enzyme (eg, CYP3A4). If the designation is
printed in italics, it represents the gene associated with
the enzyme (eg, CYP3A4). CYP1, CYP2, and CYP3 are
the three families responsible for most drug and
carcinogen metabolism.
1
The CYP1 family may also
play a role in carcinogenic activation,
1
whereas CYP2
and CYP3 are characterized by their inducibility by
different medications such as phenobarbital
3,4
and
their ability to metabolize a wide variety of drugs
(Table 1).
1,5
Drugs that are metabolized by the same CYP450
enzyme family, when administered concurrently, may
interact and affect systemic clearance of each other. The
nature, extent, and clinical signicance of these inter-
actions also depend on whether the interacting agents
are substrates, inducers, or inhibitors of the CYP450
enzyme. Genetic polymorphism in the functional
expression of some CYP450 enzymes, such as CYP2D6,
also plays a signicant role in determining interpatient
variability in the degree of drug metabolism. Other
factors such as age, nutrition, stress, hepatic disease,
hormones, and other endogenous chemicals also play
a role in determining the signicance of the drug
interaction.
SUBSTRATES, INHIBITORS, AND
INDUCERS
A CYP450 substrate is an exogenous or endogenous
substance 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 Medical
Center, New York, NY; and
2
Department 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: WSAronow@aol.com
American Journal of Therapeutics 00, 000000 (2009)
10752765 2009 Lippincott Williams & Wilkins
be metabolized by more than one CYP450 enzyme and
are considered substrates for multiple enzymes. For
example, tricyclic antidepressants are metabolized by
CYP2D6, 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 to
occur because of shared metabolism among enzymes.
A CYP450 inhibitor is an exogenous or endogenous
substance that will inhibit the activity of the CYP450
enzymes but may not necessarily be metabolized by
the enzymes themselves (eg, cimetidine). Inhibition
occurs as a result of competitive binding at the en-
zymes binding site, which prevents the enzyme from
metabolizing other agents. The onset and offset of
enzyme inhibition by an individual inhibitor are
dependent on the half-life of the inhibitor. For example,
cimetidine ( with a half-life of approximately 2 hours
and inhibits CYP1A2) inhibits drug metabolism by
CYP1A2 within 24 hours of a single dose administration.
But its inhibitory effect will also disappear within 24
hours of drug discontinuation. On the other hand,
amiodarones (with a half-life of 30 to 60 days and
inhibits CYP2C9) inhibitory action may not take place
for months because of its long half-life, and its
inhibitory effect will also last for months after drug
discontinuation.
6
Likewise, a CYP450 inducer is an
agent that will increase the activity of CYP450 enzymes
but also may not necessarily be metabolized by the
enzymes themselves (eg, phenobarbital). Similarly to
inhibitors, the onset of enzyme induction is dependent
on the half-life of the inducer agent. In addition, the
time course of induction is also dependent on the time
required for new enzyme production as well as
a 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, methadone
CYP2C8 Paclitaxel, torsemide, repaglinide
CYP2C9 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-tetrahydrocannabinol
CYP2C19 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, theophylline
CYP3A3 Benzphetamine, erythromycin, cyclosporin, vinca alkaloids
CYP3A4, 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
major inhibitors and inducers of different CYP450
enzymes.
1,5
CLINICALLY SIGNIFICANT CYP450
CARDIOVASCULAR DRUG
INTERACTIONS
Angiotensin II receptor antagonists
Two of the angiotensin II receptor antagonists currently
available on the market (losartan, irbesartan) are
metabolized by CYP2C9 (primarily) and CYP3A4 (to
a minor extent). Although no signicant clinical drug
interactions have been reported to date, signicant
inhibition of these two enzymes by other agents can
potentially inhibit their metabolism, and therefore
careful monitoring of toxicity is required. It has been
reported that rifampin, by inducing CYP2C9 and
CYP3A4 activities, decreases the half-life of losartan
and its metabolite by 50% in healthy volunteers.
7
It has
also been demonstrated that when uconazole, a potent
CYP2C9 inhibitor, was administered daily for 20 days
to 16 male subjects who received daily doses of
losartan, it signicantly raised plasma concentrations
of losartan and inhibited formation of the active
metabolite.
8
These changes in plasma concentrations
of the active drugs and metabolites, however, did not
produce signicant changes in clinical response such as
reduction in blood pressure.
Antiarrhythmic drugs
Quinidine is itself metabolized by the CYP3A4 enzyme
but inhibits CYP 2D6. CYP3A4 interactions with
quinidine that are well documented include those with
cimetidine, phenytoin, phenobarbital, and rifampin.
912
Signicant interaction has also been reported between
quinidine and erythromycin.
13
Erythromycin has been
reported to increase quinidine concentrations by 142%.
Quinidine concentrations should be monitored and
patients assessed for signs of toxicity in these situations.
Amiodarone is also metabolized by the CYP3A4
enzymes. Phenytoin, by inducing CYP3A4, has been
reported to enhance amiodarone metabolism and
decrease plasma concentrations by as much as 49%.
14
On the other hand, amiodarone inhibits CYP2C9, thus
inhibiting phenytoin metabolism, resulting in doubling
plasma 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 interacts
with 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, smoking
CYP2B6 Ticlopidine Phenobarbital, rifampin
CYP2C8 Trimethoprim, glitazones, gembrozil, montelukast Rifampin
CYP2C9 Amiodarone, fenobrate, 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.
American Journal of Therapeutics (2009) 00(0)
CYP450 Cardiovascular Drug Interactions 3
QT intervals. Quinidine clearance is reduced by
amiodarone, and plasma concentrations of quinidine
may increase by 32%when administered concurrently.
17
In addition, amiodarone may increase plasma concen-
trations of hepatically metabolized beta-blockers and
calcium channel blockers. When the agents are admin-
istered concomitantly, decreasing the doses of each
agent may be necessary. Antidepressants such as
uvoxamine, uoxetine, sertraline, and nefazodone
have high CYP450 inhibitory potential and may
decrease amiodarone metabolism, thus increasing
amiodarone plasma concentrations.
18
Antiplatelet drugs
Clopidogrel is a prodrug that requires in vivo
conversion by CYP3A4 to an active metabolite (an
unstable thiol compound) to exert its antiplatelet
effect.
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 the
loading dose of clopidogrel in inhibiting platelet
aggregation after coronary artery angioplasty, it was
observed that the effectiveness of clopidogrel was
diminished in patients who were taking atorvastatin.
22
The average platelet aggregation of patients receiving
clopidogrel alone was 42% compared with those
who received clopidogrel and atorvastatin (68%, P =
0.03). Another study evaluated the ability of clopi-
dogrel in inhibiting platelet aggregation in patients
taking either atorvastatin, a CYP3A4 inhibitor, or
pravastatin, a non-CYP3A4 inhibitor.
23
Forty-four
patients undergoing coronary artery stent implanta-
tion treated with clopidogrel demonstrated that the
degree of platelet aggregation inhibition achieved
24 hours after clopidogrel administration was signif-
icantly attenuated by atorvastatin as compared with
the controls (77% aggregation with atorvastatin vs.
34%aggregation with placebo; P ,0.0001). In contrast,
clopidogrel inhibited platelet aggregation in both
the 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 in
patients with peripheral arterial disease through its
antiplatelet activity. Cilostazil is metabolized by CYP
1A2, 2D6, 3A, and 2C19. Its drug interaction prole has
not been fully elucidated. A study demonstrated that
after erythromycin coadministration, cilostazol maxi-
mum plasma concentration increased signicantly by
47%. 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 strongly
affected by CY P450 inducers and inhibitors.
25
For
example, rifampin causes a two- to threefold increase in
propranolol clearance, which lowers plasma propran-
olol concentrations to subtherapeutic levels.
26
Quini-
dine inhibits CYP2D6 activity, thus inhibiting hepatic
metabolism of propranolol and raising its plasma
concentrations.
26
Other clinically relevant drug inter-
actions involving beta-blockers include cimetidine,
which leads to additional reduction in heart rate and
intraocular pressure when administered together with
timolol ophthalmic solution by inhibiting CYP2D6.
27,28
Calcium channel blockers
Most calcium channel blockers are metabolized exten-
sively by CYP450 enzymes. When concurrent therapies
of potent CYP450 inhibitors are required, the patient
should be monitored for signs of toxicity (hypotension,
bradycardia, or tachycardia) and the dosage of calcium
channel blocker decreased, if necessary. On the other
hand, when potent CYP450 inducers are administered
concurrently with calciumchannel blockers, the dosage
may have to be increased to achieve optimal thera-
peutic effects.
Clinically signicant drug interactions caused by
enzyme inhibition reported for calcium channel block-
ers include that occurring with grapefruit juice, a potent
CYP3A4 inhibitor. Grapefruit juice, 200 to 250 mL,
when administered with felodipine, increased the area
under 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 when
felodipine (10 mg/day) was administered with oral
erythromycin 250 mg twice daily. Patients developed
ushing, ankle and leg edema, as well as tachycardia.
31
Other reports also documented substantial peripheral
edema or elevated felodipine serum concentrations
when administered concurrently with itraconazole
200 mg daily. This was also associated with statistically
signicant changes in systolic and diastolic blood
pressures and heart rate.
32
Daily doses of cimetidine
(8001200 mg) signicantly increased the mean total
area under the plasma nifedipine concentration time
curve. Corresponding to this increase in the bio-
availability of nifedipine caused by cimetidine, longer
duration of changes in heart rate were observed
in patients in the standing position.
33,34
These ndings
indicate that doses of nifedipine should be reduced
by 50% when the drug is coadministered with
cimetidine.
American Journal of Therapeutics (2009) 00(0)
4 Cheng et al
Signicant drug interactions with calcium channel
blockers caused by enzyme induction by other agents
include 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 mg
increased the bioavailability of cyclosporine and
resulted in the need for a lower dose to maintain
efcacy or avoid toxic effects.
37
Because cyclosporine is
an expensive drug, the coprescribing of diltiazem and
cyclosporine is a way of reducing the high costs of
cyclosporine.
38
Similarly, the verapamil-induced change
in cyclosporine pharmacokinetics allows the dose of
cyclosporine to be reduced by one third to one half.
39
Verapamil signicantly increased mean peak serum
concentration and bioavailability of simvastatin.
40
This
interaction probably results from the inhibition of
CYP3A4 or P-glycoprotein by verapamil. Although the
clinical signicance of this nding is not clear, the
manufacturer of simvastatin recommends to avoid
concurrent use of simvastatin and verapamil, and if the
two agents must be used together, the dose of
simvastatin be kept at a maximum of 20 mg.
41
One
meta-analysis suggested that, overall, calcium channel
blockers do not increase the risk of myopathy when
used concomitantly with simvastatin.
42
Diltiazem inhibits the metabolism of triazolam,
probably by inhibiting the activity of CYP3A.
43
When
patients using diltiazem were anesthetized with large
doses of midazolam, a signicant delay in tracheal
extubation was attributed to reduced metabolism of
these anesthetics secondary to inhibition of CYP3A by
diltiazem.
44
Similarly, diltiazem increased plasma
levels of methylprednisolone, which enhanced sup-
pression of morning plasma cortisol levels. This nding
suggests 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 are
metabolized by the CYP450 system (CPY2C4 and
CYP3A4, respectively). A clinically signicant drug
interaction of torsemide involving the CYP450 system
has not been reported. Eplerenone is metabolized
primarily by CYP3A4. A potent inhibitor of CYP3A4
such as ketoconazole increased serum concentra-
tion of eplerenone by vefold, whereas less potent
CYP3A4 inhibitors such as erythromycin and vera-
pamil increased serum concentration of eplerenone by
threefold. The administration of grapefruit juice with
eplerenone was reported to increase serum eplerenone
concentration by 25%.
46
3-hydroxy-3-methylglutaryl coenzyme a reductase
inhibitors
Three of the six 3-hydroxy-3-methylglutaryl coenzyme
A (HMG-CoA) reductase inhibitors marketed in the
United States are metabolized primarily by CYP3A4
(atorvastatin, lovastatin, simvastatin). Dose-related
toxic effects on skeletal muscle are well documented
with HMG-CoA reductase inhibitors.
47
Risk of de-
veloping rhabdomyolysis increases as this class of drug
is used in combination with other CYP3A4 inhibitor
agents that compete with CYP3A4 metabolism (eg,
cyclosporin, gembrozil, niacin, erythromycin).
48,49
As
mentioned in the previous section on calcium channel
blockers, the manufacturer of simvastatin has made
several recommendations of daily maximum doses of
simvastatin use when it is administered concurrently
with several CYP3A4 inhibitors.
41
When administered
concurrently with verapamil or amiodarone, the max-
imum dosage of simvastatin used should not exceed
20 mg per day to minimize the risk of myopathy. When
administered with cyclosporin, danazol, and gem-
brozil, the maximum daily dose of simvastatin usage
should not exceed 10 mg.
Bleeding or prolonged prothrombin time was
reported in several patients taking HMG-CoA reduc-
tase inhibitor (those metabolized by CYP3A4) concomi-
tantly with warfarin.
50
Fluvastatin and pravastatin, on
the other hand, have not been reported to interact with
warfarin.
Warfarin
Warfarin has an extensive drug interaction prole.
R-warfarin is a substrate of CYP3A4. Therefore, any
medications that are inducers or inhibitors of CYP3A4
will interact with R-warfarin pharmacokinetically.
Fluconazole, itraconazole, and ketoconazole have been
reported to increase the anticoagulant effects of
warfarin by two- to three fold.
5153
Numerous reports
describe the enhancement of the hypoprothrombine-
mic effects (up to 2-fold) of warfarin when given in
combination with erythromycin and clarithromy-
cin.
54,55
Azithromycin has not been reported to have
such an interaction. The clinical relevance of any
warfarin interactions depends on many other patient
factors including age, rates of warfarin clearance, and
other concurrent drug therapy.
Omeprazole, a proton pump inhibitor, inhibits the
metabolism 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 be
dose related. This effect does not abate until several
days after discontinuation of omeprazole.
56
Careful
drug monitoring is therefore required.
American Journal of Therapeutics (2009) 00(0)
CYP450 Cardiovascular Drug Interactions 5
CLINICALLY SIGNIFICANT CYP450
NONCARDIOVASCULAR DRUG
INTERACTIONS THAT PRODUCE
CARDIOVASCULAR 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 newer
generation atypical antipsychotics, are substrates of
CYP450 enzymes but neither inhibit nor induce the
CYP450 enzymes. Coadministration of SSRI with
tricyclic antidepressants and antiarrhythmics have
been reported to increase the risk of developing
Torsades de Pointes.
57,58
Several studies have docu-
mented that uvoxamine, a new SSRI, may elevate
plasma levels of olanzapine by approximately two
times, presumably through inhibition of CYP1A2,
with possible occurrence of unwanted effects. In
particular, in eight patients stabilized on olanzapine
therapy (1020 mg/day), the addition of uvoxamine
(100 mg/day) for 8 weeks increased plasma olanzapine
levels by approximately 80%, which increased the
incidence of sedation, orthostatic hypotension, tachy-
cardia, and elevation of transaminase.
59
Antihistamines
Both terfenidine and aztemizole are two rst-generation
nonsedating antihistamines that have been removed
fromthe market because of their serious cardiovascular
drug interaction. Terfenidine and aztemizole are
substrates of CYP3A4. Terfenidine was rst reported
to cause QT interval prolongation and Torsades de
Pointes when coadministered with ketoconazole in
1990.
60
A prospective study of six healthy volunteers
given the combination were noted to have increased
terfenidine 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. This
leads to increased serum concentration of the parent
compound, terfenidine, which is arrhythmogenic.
Other antifungal agents such as itraconazole and
uconazole have less inhibitory effect on CYP3A4.
62
Therefore, in dosages used clinically, the incidence of
arrhythmia is low.
63
Astemizole undergoes extensive
rst-pass metabolism to form active metabolites, and
similar to terfenidine, the parent compound is also the
cardiotoxic entity. Therefore, in many circumstances,
drug interactions of terfenidine have been extrapolated
to astemizole.
64
Erythromycin is another inhibitor of CYP3A4
enzyme and in itself can also cause QT prolongation.
64
Therefore, when coadministered with terfenidine or
aztemizole, it may increase the risk of arrhythmia.
65
This effect was also reported with clarithromycin but
not with azithromycin.
66
Because the accumulations of terfenadine and
aztemizole can lead to prolongation of QT intervals
and devastating arrhythmias, coadministration of these
antihistamines with other agents that are also capable
of prolonging QT will, through a pharmacodynamic
interaction, increase the risk of developing Torsades de
Pointes. Agents that are known to prolong QTintervals
are listed in Table 3.
67
Antimicrobials and antifungals
Macrolides (except azithromycin) are substrates and
inhibitors of CYP3A4. Coadministration of CYP3A
inhibitors (antifungal agents, diltiazem, verapamil, and
troleandomycin) with erythromycin has been associ-
ated with a doubling of the risk of sudden cardiac death
caused by increased concentrations of erythromycin.
68
Ketoconazole, itraconazole, uconazole, and vorico-
nazole have been shown to prolong the QT interval and
to be associated with Torsades, with the majority of
reports of Torsades stemming from CYP450 involving
drug interactions and relating to ketoconazole and
itraconazole.
6973
In addition, allelic polymorphisms of
CYP2C19 have demonstrated the greatest impact on
voriconazole clearance, resulting in either poor or
extensive metabolism of this drug and leading some
to 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 records
of more than 13,000 patients to cause tachycardia,
Table 3. Pharmacologic agents capable of prolonging
QT intervals.
41
Antiarrhythmics
Antipsychotics
Chloroquin
Cisapride
Droperidol
Tricyclic antidepressants
Fluconazole
Itraconazole
Ketoconazole
Macrolides (erythromycin, clarithomycin)
Methadone
Pentamadine
American Journal of Therapeutics (2009) 00(0)
6 Cheng et al
palpitations, and extrasystoles.
75
Postulations of the
cause of tachycardia include activation of serotonin-4
receptors on the myocardium and prolonged atrioven-
tricular conduction because of its structural similarity to
procainamide. The rst report of arrhythmia drug
interaction was reported between cisapride and eryth-
romycin. The patient developed prolonged QT interval
with progression to Torsades.
76
Since then, Janssen
Pharmaceutical, who markets cisapride, continues to
receive numerous reports of Torsades. More than 50%
of these patients were concomitantly receiving other
medications that may prolong QT intervals.
77
The
mechanism of these interactions is believed to be
competitive binding and inhibition of CYP3A4 enzyme
by cisapride. In 2000, Janssen Pharmaceutical decided
to stop marketing Cisapride in the United States but
continued to make the drug available to those patients
whom their physicians still considered to receive
benets from cisapride that outweighed its risks.
78
Grapefruit juice
Grapefruit juice is a potent inhibitor of gut wall
CYP3A4, which is important in metabolism of all
dihydropyridines, HMG-CoA reductase inhibitors,
cisapride, midazolam, and cyclosporin. It is now
known that grapefruit juice on average increases
felodipine area under the curve by 240% and increases
nisoldipine peak plasma concentration by vefold.
79,80
In addition to CYP3A4, grapefruit juice has also
demonstrated to signicantly inhibit CYP1A2.
80
This
will be of particular importance in patients taking
propafenone and warfarin.
Methadone
Recent studies and case series have associated the use
of methadone with development of prolonged QT
intervals and Torsades.
81
Methadone is metabolized by
CYP3A4 and to a lesser extent CYP2D6. Therefore,
coadministration of methadone with agents that inhibit
CYP3A4 and CYP2D6 may increase the risk of
Torsades. In a case control study examining 40 patients
with reported methadone-induced Torsades de
Pointes, the concurrent use of agents that inhibit
CYP3A4 increase the risk of Torsades by 55%.
82
In
one 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 improved
understanding of the CYP450 system, their substrates,
inhibitors, and inducers allow us to predict potential
drug interactions. This review discusses the general
principles of occurrence of these interactions with
selected published signicant examples. Continued
in vivo drug interaction studies and reporting by clini-
cians are necessary to establish the clinical signicance
of these interactions and will help to prevent and
manage these drug interactions.
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