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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 significant clinical consequences may occur. This review discusses CYP450-
mediated cardiovascular drug interactions as well as noncardiovascular drug interactions that
produced significant cardiovascular side effects. The principles in predicting drug interactions are
also discussed.
INTRODUCTION the enzyme (eg, CYP3A4). CYP1, CYP2, and CYP3 are
the three families responsible for most drug and
Cytochrome P (CYP) 450 is a superfamily of hemo- carcinogen metabolism.1 The CYP1 family may also
proteins found in human liver and other tissues such as play a role in carcinogenic activation,1 whereas CYP2
the gastrointestinal tract that play an important role in and CYP3 are characterized by their inducibility by
the metabolism of steroid hormones and fatty acids.1 different medications such as phenobarbital3,4 and
Its name was derived from its spectral absorbance their ability to metabolize a wide variety of drugs
maximally produced near 450 nm when carbon mon- (Table 1).1,5
oxide binds to the enzyme at its reduced state. CYP450 Drugs that are metabolized by the same CYP450
also plays a part in the metabolism of various drugs enzyme family, when administered concurrently, may
and exogenous chemicals.1 Within the P450 superfam- interact and affect systemic clearance of each other. The
ily, families are designated by Arabic numeral (eg, nature, extent, and clinical significance of these inter-
CYP3). Members of the same family have to have more actions also depend on whether the interacting agents
than 40% identical amino acid sequence.2 If the amino are substrates, inducers, or inhibitors of the CYP450
acid sequence is more than 55% identical, they will be enzyme. Genetic polymorphism in the functional
categorized as a subfamily (eg, CYP3A). An Arabic expression of some CYP450 enzymes, such as CYP2D6,
numeral is added to the subfamily to identify each also plays a significant role in determining interpatient
individual enzyme (eg, CYP3A4). If the designation is variability in the degree of drug metabolism. Other
printed in italics, it represents the gene associated with factors such as age, nutrition, stress, hepatic disease,
hormones, and other endogenous chemicals also play
a role in determining the significance of the drug
interaction.
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 2Department of Medicine, New York SUBSTRATES, INHIBITORS, AND
Medical College/Westchester Medical Center, Valhalla, NY. INDUCERS
*Address for correspondence: Cardiology Division, New York
Medical College, Macy Pavilion, Room 138, Valhalla, NY 10595.
E-mail: WSAronow@aol.com A CYP450 substrate is an exogenous or endogenous
substance metabolized by CYP450. Some drugs may
1075–2765 Ó 2009 Lippincott Williams & Wilkins
156 Cheng et al
be metabolized by more than one CYP450 enzyme and and inhibits CYP1A2) inhibits drug metabolism by
are considered substrates for multiple enzymes. For CYP1A2 within 24 hours of a single dose administration.
example, tricyclic antidepressants are metabolized by But its inhibitory effect will also disappear within 24
CYP2D6, CYP1A2, and CYP3A4.5 In this situation, hours of drug discontinuation. On the other hand,
when one of the enzymes is inhibited by another agent, amiodarone’s (with a half-life of 30 to 60 days and
a clinically significant interaction may be less likely to inhibits CYP2C9) inhibitory action may not take place
occur because of shared metabolism among enzymes. for months because of its long half-life, and its
A CYP450 inhibitor is an exogenous or endogenous inhibitory effect will also last for months after drug
substance that will inhibit the activity of the CYP450 discontinuation.6 Likewise, a CYP450 inducer is an
enzymes but may not necessarily be metabolized by agent that will increase the activity of CYP450 enzymes
the enzymes themselves (eg, cimetidine). Inhibition but also may not necessarily be metabolized by the
occurs as a result of competitive binding at the en- enzymes themselves (eg, phenobarbital). Similarly to
zymeÔs binding site, which prevents the enzyme from inhibitors, the onset of enzyme induction is dependent
metabolizing other agents. The onset and offset of on the half-life of the inducer agent. In addition, the
enzyme inhibition by an individual inhibitor are time course of induction is also dependent on the time
dependent on the half-life of the inhibitor. For example, required for new enzyme production as well as
cimetidine ( with a half-life of approximately 2 hours a patients’ age and liver function. Table 2 lists some
American Journal of Therapeutics (2009) 16(2)
CYP450 Cardiovascular Drug Interactions 157
major inhibitors and inducers of different CYP450 of the active drugs and metabolites, however, did not
enzymes.1,5 produce significant changes in clinical response such as
reduction in blood pressure.
CLINICALLY SIGNIFICANT CYP450
Antiarrhythmic drugs
CARDIOVASCULAR DRUG
INTERACTIONS Quinidine is itself metabolized by the CYP3A4 enzyme
but inhibits CYP2D6. CYP3A4 interactions with quin-
idine that are well documented include those with
Angiotensin II receptor antagonists
cimetidine, phenytoin, phenobarbital, and rifampin.9–12
Two of the angiotensin II receptor antagonists currently Significant interaction has also been reported between
available on the market (losartan, irbesartan) are quinidine and erythromycin.13 Erythromycin has been
metabolized by CYP2C9 (primarily) and CYP3A4 (to reported to increase quinidine concentrations by 142%.
a minor extent). Although no significant clinical drug Quinidine concentrations should be monitored and
interactions have been reported to date, significant patients assessed for signs of toxicity in these situations.
inhibition of these two enzymes by other agents can Amiodarone is also metabolized by the CYP3A4
potentially inhibit their metabolism, and therefore enzymes. Phenytoin, by inducing CYP3A4, has been
careful monitoring of toxicity is required. It has been reported to enhance amiodarone metabolism and
reported that rifampin, by inducing CYP2C9 and decrease plasma concentrations by as much as 49%.14
CYP3A4 activities, decreases the half-life of losartan On the other hand, amiodarone inhibits CYP2C9, thus
and its metabolite by 50% in healthy volunteers.7 It has inhibiting phenytoin metabolism, resulting in doubling
also been demonstrated that when fluconazole, a potent plasma phenytoin levels.15 When amiodarone is ad-
CYP2C9 inhibitor, was administered daily for 20 days ministered concurrently with warfarin therapy, pro-
to 16 male subjects who received daily doses of thrombin time may double in 3 to 4 days.16 This is
losartan, it significantly raised plasma concentrations because warfarin is partially metabolized by CYP2C9,
of losartan and inhibited formation of the active as with phenytoin. Similarly, quinidine also interacts
metabolite.8 These changes in plasma concentrations with amiodarone, resulting in significantly prolonged
palpitations, and extrasystoles.75 Postulations of the inhibitors, and inducers allow us to predict potential
cause of tachycardia include activation of serotonin-4 drug interactions. This review discusses the general
receptors on the myocardium and prolonged atrioven- principles of occurrence of these interactions with
tricular conduction because of its structural similarity to selected published significant examples. Continued
procainamide. The first report of arrhythmia drug in vivo drug interaction studies and reporting by clini-
interaction was reported between cisapride and eryth- cians are necessary to establish the clinical significance
romycin. The patient developed prolonged QT interval of these interactions and will help to prevent and
with progression to Torsades.76 Since then, Janssen manage these drug interactions.
Pharmaceutical, who markets cisapride, continues to
receive numerous reports of Torsades. More than 50%
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