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Implications of Cytochrome P450 Interactions When Prescribing Medication for Hypertension
David A. Flockhart, MD, PhD;
Jose E. Tanus-Santos, MD, PhD
Arch Intern Med. 2002;162:405-412.
ABSTRACT
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Many of the estimated 50 million Americans with high blood pressure
receive medications for hypertension and for other conditions, placing them
at risk for adverse drug interactions. The risk for hypertension and for adverse
drug reactions is highest in the elderly, who have the greatest need for pharmacologic
therapy. The most important class of drug interactions involves the cytochrome
P450 microsomal enzyme system, which handles a variety of xenobiotic substances.
A potential for interactions with these enzymes exists with calcium channel
blockers,  -adrenergic blocking agents, angiotensin-converting enzyme
inhibitors, and angiotensin receptor blockers but not with diuretic antihypertensives,
which are renally eliminated and more vulnerable to drug interactions that
occur in the kidney. This article reviews the cytochrome P450 enzyme system,
identifies drugs and foods that have been implicated in metabolic interactions
with antihypertensive agents, and suggests measures for reducing the risk
of adverse events when drugs are coadministered.
INTRODUCTION
An estimated 50 million Americans have hypertension.1
Although the benefits of antihypertensive therapy are well established, it
is clear that treatment with more than 1 drug may be necessary to achieve
satisfactory blood pressure control. Moreover, many patients with hypertension
require medication therapy for other diseases or conditions. The intersection
of the high prevalence of hypertension, combination antihypertensive therapy,
and drug-treated comorbid conditions results in the possibility of many drug
interactions. The elderly are particularly vulnerable. Not only does this
population take the most medications, but it also undergoes age-related changes
in body and organ mass and in cardiac, hepatic, and renal function.2 Findings from one review3
indicate that adverse drug reactions account for 10% to 17% of the medical
reasons for acute hospital admission of elderly patients. The importance of
adverse drug reactions as a cause of morbidity and mortality in the United
States has been emphasized by several recent studies4-5
that have made clear that more than 100 000 deaths result from adverse
drug reactions each year in US hospitals, representing the fourth to sixth
leading cause of death. The adverse effects of drugs and drug interactions
are of great importance to patients. Being prescribed the wrong drug or drugs
that interact is among the primary concerns of patients as they enter a physician's
office.6
INTERACTIONS RESULTING IN REMOVAL OF DRUGS FROM THE MARKET
The novel calcium channel blocker mibefradil dihydrochloride (Posicor;
Hoffmann-LaRoche Inc, Nutley, NJ) was withdrawn from the market because of
potentially dangerous interactions when it was coprescribed with any of more
than 25 drugs, some of them resulting in rhabdomyolysis, renal failure, and
death.7-8 Terfenadine (Seldane;
Marion Merrell Dow Inc, Kansas City, Mo) and astemizole (Hismanal; Janssen
Pharmaceutica, Titusville, NJ), widely prescribed antihistamines, were also
withdrawn. These agents serve as substrates for cytochrome P450 3A, whose
inhibition by ketoconazole or several macrolide antibiotics may result in
prolongation of the electrocardiographic QT interval and lethal cardiotoxicity.9-10 The combination of cisapride, the
oral gastrointestinal tract prokinetic agent used for the treatment of gastroesophageal
reflux disease, with several drugs that elevate its plasma concentrations
has resulted in serious and sometimes fatal ventricular arrhythmias, including
torsade de pointes. Therefore, concomitant use of cisapride with the antibiotics
clarithromycin, erythromycin, and troleandomycin; the antidepressant nefazodone
hydrochloride; the antifungals fluconazole, ketoconazole, and itraconazole;
and the protease inhibitors indinavir sulfate and ritonavir is contraindicated.11 There is a longer list of other drugs that must be
prescribed with great caution to patients receiving cisapride. Numerous warnings
to physicians and health care providers about potentially lethal drug interactions
with cisapride did not improve appropriate prescribing of the drug. It became
clear that more than 30% of the prescriptions were inappropriate,12 and sale of the drug in the United States was restricted
by the manufacturer and the Food and Drug Administration in July 2000.13 The recent series of drug withdrawals owing to drug
interactions seems to emphasize the importance of educating physicians, nurses,
pharmacists, and their patients about drug interactions, but it also makes
abundantly clear that we do not have effective means of doing so at present.
The information compiled by the Institute of Medicine titled To Err Is Human14 made clear that preventable
drug interactions contribute significantly to the burden of iatrogenic disease
and that the danger of this situation worsening is considerable as the number
of medicines available to an aging population increases.
ADVERSE DRUG INTERACTIONS DUE TO ANTIHYPERTENSIVE DRUGS
Drug interactions with many antihypertensive agents that are metabolized
by the cytochrome P450 system have been reported. For example, cimetidine
hydrochloride can decrease metabolism and increase steady-state plasma concentrations
of several concomitantly administered drugs, including calcium channel blockers.15 Azole antifungal agents such as ketoconazole and
fluconazole can also affect the metabolism of calcium channel blockers and
some angiotensin II receptor blockers.16 Even
grapefruit juice can increase drug bioavailability via the cytochrome P450
system.17 This article reviews the mechanisms
of the microsomal enzyme system that contribute to normal metabolism and drug
interactions, identifies a variety of drugs implicated in interactions with
antihypertensive agents, and suggests measures for reducing the risk of adverse
events when other drugs are coadministered with antihypertensive agents.
For pharmacokinetic reasons, most orally administered drugs are lipid
soluble and nonpolar rather than hydrophilic and polar. Once absorbed, lipophilic
drugs undergo a 2-stage biotransformation in the liver. In phase I, they are
converted to active or inactive metabolites. However, because excretion ultimately
depends on aqueous solubility in urine or feces, many drugs and their active
metabolites undergo a second biotransformation (phase II) to render them polar
and hydrophilic. Highly hydrophilic drugs (eg, atenolol and nadolol), on the
other hand, generally escape hepatic metabolism and are excreted largely unchanged
in urine. Many orally administered drugs are actually prodrugs, exerting all
or most of their pharmacologic effect only on conversion to active metabolites
(eg, quinapril hydrochloride to quinaprilat and losartan potassium to a carboxylic
acid metabolite).
Most important phase I reactions are catalyzed by the cytochrome P450
microsomal enzymes, a set of heme-containing proteins localized primarily
in hepatocytes but also in the intestines.18-19
Collectively, these enzymes catalyze oxidative and reductive reactions on
a variety of substrates (ie, the drugs or other xenobiotic substances that
are acted on). Some drugs are substrates for only 1 enzyme, whereas others
are substrates for more than 1. Certain drugs act on enzymes that metabolize
other substrates in a way that has lasting effects; these are the agents most
likely to be involved in clinically important drug interactions.
The nomenclature for cytochrome P450 enzymes is based on how homologous
their amino acid sequences are.19-20
A hierarchy of cytochrome P450 classification (designated with the prefix
CYP) proceeds from the family (designated by Arabic numerals) to the subfamily
(designated by capital letters) to individual isoforms (designated by Arabic
numerals), eg, CYP3A4. Although hundreds of cytochromes P450 have been identified,
only 6 isoforms catalyze the oxidative metabolism of most drugs in common
use: CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4.21 Figure 1 depicts the proportion of drugs
metabolized by the major cytochrome P450 isoforms. Extensive metabolism by
CYP3A4 in the intestinal mucosa and the liver contributes to the low oral
bioavailability of many drugs.19
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Proportion of drugs metabolized by the major cytochrome P450 isozymes.
The value for CYP2C metabolism reflects contributions by CYP2C9, CYP2C10,
CYP2C18, and CYP2C19. Adapted from Hardman JG, Gilman AG, Limbird LE, eds.
Goodman and Gilman's The Pharmacological Basis of
Therapeutics. 9th ed. New York, NY: McGraw-Hill Health Professions
Division; 1996.19
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Two major mechanisms are responsible for cytochrome P450–mediated
drug interactions: induction and potent inhibition. Induction refers to increased
synthesis or decreased degradation of cytochrome P450 enzymes, actions that
expedite conversion to inactive metabolites. Thus, induction results in decreased
plasma levels of the substrate and a decrease in its pharmacodynamic effect.
Examples of inducers are rifampin and phenobarbital, which decrease the bioavailability
of propranolol hydrochloride, metoprolol succinate, and calcium channel blockers. Table 1 lists drugs that induce or inhibit
cytochrome P450 enzymes for antihypertensive agents.22-23
Smoking delivers chemicals that induce CYP1A2, but it has little effect on
the hepatic metabolism of antihypertensive agents.
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Table 1. Some Drugs That Interact Metabolically With Antihypertensive
Drugs*
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Inhibition refers to either enzyme inactivation or mutual competition
of substrates for a catalytic site. Both responses have the net effect of
decreasing the rate of drug metabolism and thereby prolonging the half-life
of the affected drug or active metabolite and amplifying its pharmacodynamic
(or toxic) effect. Examples of inhibitors are fluconazole and erythromycin.
Examples of substrates whose bioavailability is potently increased by inhibitors
are 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins,"
except pravastatin sodium, fluvastatin sodium, and cerivastatin sodium). Antidepressants
such as fluoxetine hydrochloride and paroxetine are active inhibitors of the
metabolism of CYP2D6 substrates, whereas antifungals, macrolide antibiotics,
and grapefruit juice potently inhibit CYP3A-mediated metabolism.
The ability to metabolize a drug along a specific pathway of the cytochrome
P450 enzyme system can be modulated by genetic polymorphisms, causing some
individuals to be poor (slow) metabolizers and others to be extensive (rapid)
metabolizers. Genotyping studies24 have identified
polymorphisms in the gene coding for CYP2D6, which mediates the metabolism
of many commonly used drugs. Both poor and extensive metabolizers of debrisoquin
sulfate (a phenotyping probe for CYP2D6) may be susceptible to interactions
between tricyclic antidepressants, selective serotonin reuptake inhibitors,
neuroleptics, or antiarrhythmic drugs and other CYP2D6 substrates, including
lipophilic -renergic blocking agents. No polymorphic variations have
been detected in the genes for CYP3A3/4, although there seem to be interindividual
differences in activity.25
Among possible metabolic drug interactions, inhibition of enzyme activity
seems more relevant than induction because the former often occurs immediately,
whereas the latter usually takes time to bring about its effect. Clinically
important drug interactions commonly occur when a drug potently inhibits another
drug-metabolizing enzyme. In this regard, several of different kinds of enzyme
inhibition that can impair drug metabolism have been described:
- Competitive inhibition: This is the most common
kind of inhibition, but it is unlikely to be the most clinically relevant.
It occurs as a result of competition for the active site of an enzyme by the
inhibitor and the substrate.
- Formation of metabolite intermediate complexes:
The metabolite forms a catalytically inactive complex with the enzyme, thereby
reducing the enzyme activity. A number of important interactions that use
this mechanism have been described, most notably between diltiazem hydrochloride
and simvastatin.26-27
- Mechanism-based inhibition: A substrate is transformed
by the enzyme, and the compound formed inactivates the enzyme. This mechanism,
originally described by Ortiz de Montellano and colleagues28-29
and referred to as suicide inhibition, is characterized
by a time-dependent loss of enzyme activity and irreversible modification
of the enzyme.
DRUG INTERACTIONS BY ANTIHYPERTENSIVE CLASS
-Adrenergic Blocking Agents
The pharmacokinetics of -adrenergic blocking agents such as propranolol
is strongly affected by cytochrome P450 inducers and inhibitors.30
For example, rifampin causes a 2- to 3-fold increase in propranolol clearance,
which lowers plasma propranolol concentrations to subtherapeutic levels.31 Quinidine sulfate, on the other hand, inhibits hepatic
metabolism of propranolol by CYP2D6,thereby raising its plasma concentrations.
Many other examples of clinically relevant metabolic drug interactions involving -adrenergic
blocking agents exist. The inhibition of CYP2D6 by cimetidine may lead to
additional reductions in heart rate and intraocular pressure when cimetidine
is administered with timolol maleate ophthalmic solution.32
Similarly, because quinidine inhibits CYP2D6, an excessive -blockade
may occur after administration of timolol eye drops in patients treated with
quinidine.33 Diphenhydramine hydrochloride
inhibits the metabolism of metoprolol by CYP2D6 in extensive metabolizers,
thereby prolonging the negative chronotropic and inotropic effects of the
drug.34 Also, 8-day treatment with hydroxychloroquine
sulfate, a drug used in the treatment of chronic inflammatory diseases, significantly
increased the bioavailability and the maximal plasma concentrations of metoprolol
in 7 control subjects with extensive metabolizer phenotype for CYP2D6.35 Although ethinyl estradiol reduced the clearance
of a single dose of propranolol through cytochrome P450 oxidation, this drug
increased the clearance of propranolol through glucuronidation, with the overall
result being no change in the total clearance of this -adrenergic blocking
agent.36
Antihypertensive drugs may also interact with each other. For example,
pharmacokinetic interactions due to alterations in blood liver flow may occur
when calcium channel blockers are given concomitantly with -adrenergic
blocking agents. In this regard, metoprolol interacts with verapamil hydrochloride
in such a way that metoprolol decreases the systemic clearance of verapamil,
whereas verapamil increases metoprolol bioavailability, resulting in a need
for a lower dose of metoprolol.37
Carvedilol is a racemic mixture of R(+) and S(-) enantiomers.
The metabolism of both enantiomers seems to be catalyzed by CYP1A2, CYP2E1,
CYP2C9, and CYP3A4 in addition to CYP2D6, although the clearance of S(-)
carvedilol is faster. This complex enzymatic pattern may moderate the effect
of changes in the activity of any individual enzymes on the clearance of the
S(-) enantiomer in a given individual.38
Bisoprolol fumarate, another racemic mixture, is catalyzed by CYP3A4 in nonstereoselective
fashion and by CYP2D6 stereoselectively.39
Several other potential cytochrome P450–associated drug interactions
involving -adrenergic blocking agents remain to be elucidated. Although
water-soluble -adrenergic blocking agents, such as sotalol hydrochloride,
nadolol, and atenolol, are essentially not metabolized in the liver, and thereby
are less prone to metabolic drug interactions, many lipophilic -adrenergic
blocking agents are metabolized by CYP2D6. Clinicians should anticipate toxic
interactions of -adrenergic blocking agents when coadministered with
drugs that inhibit CYP2D6.
Calcium Channel Blockers
Calcium channel blockers serve as substrates for and inhibitors of CYP3A4.40-42 Mibefradil has a
broad range of effects on several isoforms, including prolongation or amplification
of the pharmacodynamic effects of CYP2D6 and CYP3A substrates. Because there
was a lack of information about inhibition of the drug transporter P-glycoprotein
by mibefradil,43 potential toxic metabolic
drug interactions with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
and nonsedating antihistamines were not predicted by in vitro studies of interaction
of the drug with cytochrome P450 3A.44 When
life-threatening interactions with these drugs were reported, mibefradil was
withdrawn from the market in the United States.
Some drugs may reduce the clinical effects of calcium channel blockers.
For example, treatment with rifampin (600 mg daily for 12 days) nearly abolished
the effects of orally administered verapamil (120 mg twice daily) on atrioventricular
nodal conduction. Although the enantiomers of verapamil are metabolized by
CYP3A4, CYP3A5, CYP2C8, and, to a minor extent, CYP2E1,45
the interaction of rifampin with verapamil was attributed to the induction
of CYP3A4 in the gastrointestinal tract by rifampin because no significant
interaction occurred when verapamil was administered intravenously.46-48 Similar to this interaction
with verapamil, rifampin-induced gut wall metabolism reduced the bioavailability
of nifedipine because of increased gut wall metabolism.49
The core coat formulation of nisoldipine allows its absorption across
the entire gastrointestinal tract. The significant first-pass metabolism (only
5.5% bioavailability) of this formulation makes it vulnerable to concomitant
use of drugs that induce or inhibit CYP3A450
that is well documented to be present and inducible by rifampin in the intestine.18
Other drugs may add to the effects of calcium channel blockers, and
the possibility exists that symptomatic hypotension occurs when CYP3A4 inhibitors
are given with some dihydropyridine calcium antagonists.51
In this regard, human intestinal perfusion studies52
have demonstrated that the inhibition of CYP3A4 or of P-glycoprotein by ketoconazole
increases the transport of verapamil into the circulation. Moreover, ketoconazole
potently inhibited the metabolism of nisoldipine,16
and itraconazole significantly increased plasma concentrations and effects
of oral felodipine use.53 Thus, the concomitant
use of azole antifungals with dihydropyridine calcium antagonists should be
avoided. Also, other interactions, such as the allosteric inhibitory effect
of quinidine on the metabolism of nifedipine by CYP3A,54
may increase the effects of calcium channel blockers.
Daily doses of cimetidine (800-1200 mg), but not ranitidine hydrochloride
(300 mg), significantly increased the mean ± SD total area under the
plasma nifedipine concentration time curve from 381 ± 197 to 687 ±
234 ng/h per milliliter. Corresponding to this increase in the bioavailability
of nifedipine caused by cimetidine, more marked and longer changes in heart
rate were observed in the standing position.55-56
These findings indicate that doses of nifedipine should be reduced by 50%
when this drug is coadministered with cimetidine. Also, these results suggest
that pharmacodynamic responses to most -adrenergic blocking agents or
dihydropyridine calcium channel blockers should be monitored closely when
coadministered with cimetidine.57 However,
inhibition by cimetidine is generally relatively weak, and studies55-56 that demonstrate statistically significant
pharmacokinetic changes do not prove that clinically significant pharmacodynamic
consequences inevitably ensue.
A recent study58 focused on the in vitro
inhibition of human cytochrome P450 enzymes caused by 13 clinically used dihydropyridines.
The data obtained led the researchers to suggest that important in vivo drug
interactions should occur only between nicardipine hydrochloride and other
drugs metabolized by CYP2C9 or CYP3A.58 It
was shown, however, that nifedipine, verapamil, and diltiazem decrease the
clearance of theophylline (usually by  25%).59
In addition, most calcium channel blockers studied inhibit the metabolism
of cyclosporine.60 In particular, and possibly
because of the metabolite intermediate complex that forms between diltiazem
and CYP4503A4,26 diltiazem in doses as low
as 10 mg increased the bioavailability of cyclosporine and should therefore
result in the need for a lower dose to maintain efficacy or avoid toxic effects.
Because cyclosporine is an expensive drug, the coprescription of diltiazem
and cyclosporine is a way of reducing the high costs of cyclosporine.61 Similarly, the verapamil-induced change in cyclosporine
pharmacokinetics allows the dose of cyclosporine to be reduced by one-third
to one-half.62
Verapamil significantly increased mean peak serum concentration and
bioavailability of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl
coenzyme A reductase.63 This interaction probably
resulted from the inhibition of CYP3A4 or P-glycoprotein by verapamil. Although
the clinical significance of this finding is not clear, it indicates that
this combination of drugs should be avoided or the dose of simvastatin reduced.
One meta-analysis64 suggested that calcium
channel blockers do not increase the risk of myopathy when used concomitantly
with simvastatin. This suggests that not all patients who experience a pharmacokinetic
change will encounter a clinically relevant toxic response.
Diltiazem inhibits the metabolism of triazolam,65
probably by inhibiting the activity of CYP3A. When patients using diltiazem
were anesthetized with large doses of midazolam hydrochloride and alfentanil
hydrochloride, a significant delay in tracheal extubation was attributed to
reduced metabolism of these anesthetics secondary to inhibition of CYP3A by
diltiazem.66 Similarly, either diltiazem or
mibefradil considerably increased plasma levels of methylprednisolone and
enhanced suppression of morning plasma cortisol levels. This finding suggests
that care should be taken when methylprednisolone is coadministered with diltiazem
for a long period.67
Although mibefradil and isradipine inhibit CYP3A4 in vitro, only mibefradil,
in usual clinical doses, markedly increased the peak plasma concentrations
(1.8-fold), the total area under the plasma triazolam concentration time curve
(9-fold), and the pharmacodynamic effects of triazolam.68
Moreover, the results of another study69 showed
that 5 doses of verapamil, 80 mg, or diltiazem, 60 mg, given over 2 days considerably
increased plasma buspirone hydrochloride concentrations reached after 10 mg
of this anxiolytic was given to healthy volunteers. Although 3-fold and 6-fold
increases in the area under the buspirone plasma concentration time curve
were observed with verapamil and diltiazem, respectively, only minor adverse
effects were reported for both drug interactions.69
An important interaction occurs between grapefruit juice and dihydropyridine
calcium channel blockers. For example, grapefruit juice selectively down-regulates
CYP3A4 in the small intestine wall and reduces first-pass metabolism, thereby
increasing peak serum concentration and bioavailability of felodipine.70 A more marked interaction occurs with felodipine,
nitrendipine,71 and nisoldipine,72
whereas less pronounced increases were found in the plasma concentrations
of nifedipine, nimodipine, and verapamil.73
When a single dose of felodipine (5 mg), extended release, was administered
with 250 mL of grapefruit juice to healthy elderly people, significantly lower
systolic and diastolic blood pressures were observed. The same did not occur
after 6 days of treatment with the same dose of felodipine.74-75
Angiotensin-Converting Enzyme Inhibitors
Most angiotensin-converting enzyme inhibitors (eg, benazepril hydrochloride,
cilazapril, enalapril, fosinopril sodium, perindopril erbumine, quinapril,
ramipril, and trandolapril) are prodrugs metabolized in the liver; captopril
and lisinopril are not. Some animal studies provide information suggesting
that prodrugs seem to undergo CYP3A4-dependent biotransformation.76 However, the angiotensin-converting enzyme inhibitors
are not involved in significant cytochrome P450–mediated interactions
with other drugs.
Angiotensin II Receptor Blockers
Losartan and irbesartan seem to be primarily metabolized by CYP2C9.
Incubation with human liver microsomes in vitro show that losartan is extensively
transformed by CYP2C9 and CYP3A4 (a minor effect) to an active carboxylic
acid metabolite, E-3174, that accounts for most of its angiotensin II receptor
antagonism activity. Its biotransformation is inhibited by sulfaphenazole
and ketoconazole, which act on CYP2C9 and CYP3A4, respectively.77
Indeed, reports of cytochrome P450–mediated drug interactions with the
prodrug members of this class in humans are minimal. Although erythromycin
has no effect on the pharmacokinetics of losartan, rifampin decreases the
half-life of losartan and its metabolite by 50% in healthy volunteers, an
interaction that is probably clinically significant.78
Moreover, fluconazole, a potent CYP2C9 inhibitor, was administered daily for
20 days to 16 male subjects who received daily doses of losartan. It significantly
raised plasma concentrations of losartan and inhibited formation of the active
metabolite E-3174. In contrast, fluconazole had no effect on the steady-state
pharmacokinetics of eprosartan mesylate given daily to 16 other male subjects.79
Irbesartan is metabolized mainly along the CYP2C9 pathway.77
However, unlike losartan, irbesartan does not require biotransformation to
an active metabolite, and its own metabolism is essentially unaffected by
other drugs.80 A recent in vitro study81 investigating the potential effects of 5 different
angiotensin II receptor blockers on cytochrome P450 enzymes showed that losartan
and irbesartan were the most potent inhibitors of CYP2C9, with only a small
affinity for CYP2A1 and CYP3A4. Valsartan, eprosartan, and candesartan are
not metabolized by the cytochrome P450 system and, therefore, have low potential
for drug interactions via these enzymes.
In a randomized crossover study in 12 healthy male volunteers, single
doses of cimetidine increased the maximum plasma level of coadministered valsartan
by approximately 50%. However, this pharmacokinetic perturbation was due not
to a cytochrome P450–mediated interaction but rather to inhibition of
acid secretion by the H2-receptor blocker, which increased the
rate of valsartan absorption. It is unlikely to have any important clinical
effect because valsartan is cleared mainly by biliary excretion as unchanged
drug and does not accumulate in plasma.82
There is a 49% increase in digoxin peak plasma concentration and a 20%
increase in trough digoxin concentration when coadministered with telmisartan.83 The mechanism is unknown; however, it is not thought
to be related to the cytochrome P450 system.
Other cytochrome P450 interactions involving angiotensin II blockers
remain to be elucidated. The data available now suggest that clinically relevant
interactions are more probable with losartan and irbesartan. However, further
studies are needed to clarify this issue.
Other Antihypertensive Agents
Hydrochlorothiazide and chemically related diuretics are not metabolized.
Furosemide is biotransformed to a glucuronide, and spironolactone is biotransformed
to sulfur-containing metabolites, but neither has a significant effect on
the cytochrome P450 system.
Although drugs that block  1-receptors, such as prazosin
hydrochloride and doxazosin mesylate, and clonidine hydrochloride, which blocks 2-receptors, are metabolized by the liver, they do not seem to interact
with other drugs via cytochrome P450 pathways.
MINIMIZING THE OCCURRENCE OF DRUG INTERACTIONS
Overall Precautions
Most drug interactions are preventable by forethought, although some
patient variables, such as use of over-the-counter drugs and consumption of
alcoholic beverages, are difficult to control. Inquiry about the use of over-the-counter
products and drugs prescribed by other physicians should be routine at every
visit (Table 2). Caution is particularly
appropriate when prescribing newly introduced drugs because not all interactions
can be identified in the limited number of patients enrolled in clinical trials,
and in vitro screening protocols are not perfect.84
It is important to consider any hepatic or renal dysfunction and to recognize
high-risk conditions.
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Table 2. Quick List of Guidelines to Be Remembered When Prescribing
Drugs
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Patients should be advised not to drink grapefruit juice concomitantly
with calcium channel blockers and other drugs that may raise blood levels
significantly by inhibition of CYP3A4-mediated first-pass metabolism. In addition,
caution should be taken when patients use St John's wort concomitantly with
other medications, especially those metabolized by CYP3A4.3
The physician should be aware that cimetidine may increase blood levels
of calcium channel blockers and lipophilic -adrenergic blocking agents.
Adjustments in the Elderly
Because individuals older than 65 years take the greatest number of
drugs on average, their risk of drug interactions rises. In addition, it is
not uncommon for elderly individuals to make errors at home because of poor
vision or forgetfulness, taking the wrong medication, or taking an additional
dose.
Drug dosages often have to be decreased because of age-related losses
in weight and decreases in renal and hepatic function. Also, the rate at which
drugs are oxidized by cytochrome P450 enzymes may be significantly decreased.
Although intrinsic metabolic activity per unit of liver volume probably does
not decline with age, blood flow will. Consequently, there is an increase
in the bioavailability for high-extraction drugs,85
but low-extraction drugs may be less affected.
For the foregoing reasons, physicians should try to prescribe medications
for elderly patients that allow a reasonable margin of error. With respect
to cytochrome P450–mediated drug interactions, a logical guideline in
writing a prescription might be whether the particular agent is an inducer,
inhibitor, or substrate for concomitantly administered compounds.
COMMENT
Awareness of drug interactions involving the cytochrome P450 enzyme
system has increased in the past decade. The specific isoforms involved in
drug metabolism have been identified, and genetic polymorphisms in some of
these isoforms seem to explain interindividual differences in drug metabolism.
Although this growth in the knowledge base permits physicians to predict certain
interactions more systematically, much remains to be learned as new compounds
enter the armamentarium and older ones are scrutinized more closely. Thanks
to advances in computer modeling and in vitro analysis, the metabolic profiles
of investigational agents will be better characterized before they enter clinical
trials so that the experience with mibefradil is less likely to be repeated.
It is reasonable to infer that drugs that are deemed relatively safe today
because their metabolism is not catalyzed by cytochrome P450 enzymes will
also be less likely to have adverse interactions with new drugs that enter
clinical practice in the future. Nevertheless, the importance of postmarket
surveillance should never be overlooked.
AUTHOR INFORMATION
Accepted for publication July 16, 2001.
This study was supported in part by an International Fellowship from
Merck Company Foundation, Whitehouse Station, NJ (Dr Tanus-Santos), and by
grants R01-GM56898-01 and T32-9M08386 from the National Institute of General
Medical Sciences, Bethesda, Md.
We thank Jeanne Lapsker, MD, for her editorial assistance with the manuscript.
Corresponding author and reprints: David A. Flockhart, MD, PhD, Department
of Medicine, Indiana University School of Medicine, Wishard Hospital, OPW
320, 1001 W 10th St, Indianapolis, IN 46202 (e-mail: dflockha{at}iupui.edu).
From the Division of Clinical Pharmacology, Indiana University School
of Medicine, Indianapolis. Dr Flockhart is now with the Department of Medicine,
Indiana University School of Medicine, Wishard Hospital, Indianapolis.
REFERENCES
| |
1. American Heart Association. 1999 Heart and Stroke Statistical Update. Dallas, Tex: American Heart Association; 1998.
2. Stanaszek WF, Franklin CE. Survey of potential drug interaction incidence in an outpatient clinic
population. Hosp Pharm. 1978;13:255-257, 261, 263.
PUBMED
3. Beard K. Adverse reactions as a cause of hospital admission in the aged. Drugs Aging. 1992;2:356-367.
ISI
| PUBMED
4. Bates DW, Spell N, Cullen DJ, et al. The costs of adverse drug events in hospitalized patients. JAMA. 1997;277:307-311.
FREE FULL TEXT
5. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a meta-analysis
of prospective studies. JAMA. 1998;279:1200-1205.
FREE FULL TEXT
6. American Society of Health-System Pharmacists. ASHP Patient Concerns National Survey Research Report, September 1999. Available at: http://www.ashp.org/public/public_relations/survey.html. Accessed October 11, 2000.
7. Posicor withdrawal reflects "complexity" of interaction profile. FDC Reports. June 15, 1998;The Pink Sheet:5.
8. Po ALW, Zhang WY. What lessons can be learnt from withdrawal of mibefradil from the market? Lancet. 1998;351:1829-1830.
FULL TEXT
|
ISI
| PUBMED
9. Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics
of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther. 1992;52:231-238.
ISI
| PUBMED
10. Adlakha A, Schultz H. Torsades de pointes ventricular tachycardia associated with astemizole
overdosage: report of a case and review of the literature [abstract]. Clin Res. 1992;40:856A.
11. Michalets EL, Williams CR. Drug interactions with cisapride: clinical implications. Clin Pharmacokinet. 2000;39:49-75.
FULL TEXT
|
ISI
| PUBMED
12. Smalley W, Shatin D, Wysowski DK, et al. Contraindicated use of cisapride: impact of food and drug administration
regulatory action. JAMA. 2000;284:3036-3039.
FREE FULL TEXT
13. From the Food and Drug Administration. JAMA. 2000;283:2228.
FREE FULL TEXT
14. Committee on Quality of Health Care in America, Institute of Medicine, Kohn LT, ed, Corrigan JM, ed, Donaldson MS, ed. To Err Is Human: Building a Safer Health System. Washington, DC: National Academy Press; 2000.
15. Rosenthal T, Ezra D. Calcium antagonists: drug interactions of clinical significance. Drug Saf. 1995;13:157-187.
ISI
| PUBMED
16. Heinig R, Adelmann HG, Ahr G. The effect of ketoconazole on the pharmacokinetics, pharmacodynamics
and safety of nisoldipine. Eur J Clin Pharmacol. 1999;55:57-60.
FULL TEXT
|
ISI
| PUBMED
17. Bailey DG, Malcolm J, Arnold O, Spence JD. Grapefruit juice–drug interactions. Br J Clin Pharmacol. 1998;46:101-110.
FULL TEXT
|
ISI
| PUBMED
18. Kolars JC, Schmiedlin-Ren P, Schuetz JD, Fang C, Watkins PB. Identification of rifampin-inducible P450IIIA4 (CYP3A4) in human small
bowel enterocytes. J Clin Invest. 1992;90:1871-1878.
19. Benet LZ, Kroetz DL, Sheiner LB. Pharmacokinetics: the dynamics of drug absorption, distribution, and
elimination. In: Hardman JG, Gilman AG, Limbird LE, eds. Goodman
and Gilman's The Pharmacological Basis of Therapeutics. 9th ed. New
York, NY: McGraw-Hill Health Professions Division; 1996:3-27.
20. Daly AK, Brockmoller J, Broly F, et al. Nomenclature for human CYP2D6 alleles. Pharmacogenetics. 1996;6:193-201.
ISI
| PUBMED
21. Caraco Y. Genetic determinants of drug responsiveness and drug interactions. Ther Drug Monit. 1998;20:517-524.
FULL TEXT
|
ISI
| PUBMED
22. Harvey AT, Preskorn SH. Cytochrome P450 enzymes: interpretation of their interactions with
selective serotonin reuptake inhibitors (part I). J Clin Psychopharmacol. 1996;16:273-285.
FULL TEXT
|
ISI
| PUBMED
23. Michalets EL. Update: clinically significant cytochrome P-450 drug interactions. Pharmacotherapy. 1998;18:84-112.
ISI
| PUBMED
24. Lennard MS. Genetically determined adverse drug reactions involving metabolism. Drug Saf. 1993;9:60-77.
ISI
| PUBMED
25. Watkins PB. Noninvasive tests of CYP3A enzymes. Pharmacogenetics. 1994;4:171-184.
ISI
| PUBMED
26. Jones DR, Gorski JC, Hamman MA, Mayhew BS, Rider S, Hall SD. Diltiazem inhibition of cytochrome P-450 3A activity is due to metabolite
intermediate complex formation. J Pharmacol Exp Ther. 1999;290:1116-1125.
FREE FULL TEXT
27. Mousa O, Brater DC, Sunblad KJ, Hall SD. The interaction of diltiazem with simvastatin. Clin Pharmacol Ther. 2000;67:267-274.
FULL TEXT
|
ISI
| PUBMED
28. Ortiz de Montellano PR, Mico BA, Mathews JM, Kunze KL, Miwa GT, Lu AY. Selective inactivation of cytochrome P-450 isozymes by suicide substrates. Arch Biochem Biophys. 1981;210:717-728.
FULL TEXT
|
ISI
| PUBMED
29. Ortiz de Montellano PR, Kunze KL. Self-catalyzed inactivation of hepatic cytochrome P-450 by ethynyl
substrates. J Biol Chem. 1980;255:5578-5585.
FREE FULL TEXT
30. Wood AJJ. Drug interactions in hypertension. Hypertension. 1988;11(pt 2):II-1–II-3.
31. Herman RJ, Nakamura K, Wilkinson GR, Wood AJ. Induction of propranolol metabolism by rifampicin. Br J Clin Pharmacol. 1983;16:565-569.
ISI
| PUBMED
32. Ishii Y, Nakamura K, Tsutsumi K, Kotegawa T, Nakano S, Nakatsuka K. Drug interaction between cimetidine and timolol ophthalmic solution:
effect on heart rate and intraocular pressure in healthy Japanese volunteers. J Clin Pharmacol. 2000;40:193-199.
ABSTRACT
33. Edeki TI, He H, Wood AJ. Pharmacogenetic explanation for excessive beta-blockade following timolol
eye drops: potential for oral-ophthalmic drug interaction. JAMA. 1995;274:1611-1613.
FREE FULL TEXT
34. Hamelin BA, Bouayad A, Methot J, et al. Significant interaction between the nonprescription antihistamine diphenhydramine
and the CYP2D6 substrate metoprolol in healthy men with high or low CYP2D6
activity. Clin Pharmacol Ther. 2000;67:466-477.
FULL TEXT
|
ISI
| PUBMED
35. Somer M, Kallio J, Pesonen U, Pyykko K, Huupponen R, Scheinin M. Influence of hydroxychloroquine on the bioavailability of oral metoprolol. Br J Clin Pharmacol. 2000;49:549-554.
FULL TEXT
|
ISI
| PUBMED
36. Walle T, Fagan TC, Walle UK, Topmiller MJ. Stimulatory as well as inhibitory effects of ethinyloestradiol on the
metabolic clearances of propranolol in young women. Br J Clin Pharmacol. 1996;41:305-309.
FULL TEXT
|
ISI
| PUBMED
37. Bauer LA, Horn JR, Maxon MS, Easterling TR, Shen DD, Strandness DE Jr. Effect of metoprolol and verapamil administered separately and concurrently
after single doses on liver blood flow and drug disposition. J Clin Pharmacol. 2000;40:533-543.
ABSTRACT
38. Zhou HH, Wood AJJ. Stereoselective disposition of carvedilol is determined by CYP2D6. Clin Pharmacol Ther. 1995;57:518-524.
FULL TEXT
|
ISI
| PUBMED
39. Horikiri Y, Suzuki T, Mizobe M. Stereoselective metabolism of bisoprolol enantiomers in dogs and humans. Life Sci. 1998;63:1097-1108.
FULL TEXT
|
ISI
| PUBMED
40. Bleck JS, Thiesemann C, Kliem V, et al. Diltiazem increases blood concentrations of cyclized cyclosporine metabolites
resulting in different cyclosporine metabolite patterns in stable male and
female renal allograft recipients. Br J Clin Pharmacol. 1996;41:551-556.
FULL TEXT
|
ISI
| PUBMED
41. Pichard L, Gillet G, Fabre I, et al. Identification of the rabbit and human cytochromes P-450IIIA as the
major enzymes involved in the N-demethylation of diltiazem. Drug Metab Dispos. 1990;18:711-719.
ABSTRACT
42. Guengerich FP, Brian WR, Iwasaki M, Sari MA, Bäärnhielm C, Berntsson P. Oxidation of dihydropyridine calcium channel blockers and analogues
by human liver cytochrome P-450 IIIA4. J Med Chem. 1991;34:1838-1844.
FULL TEXT
|
ISI
| PUBMED
43. Wandel C, Kim RB, Guengerich FP, Wood AJ. Mibefradil is a P-glycoprotein substrate and a potent inhibitor of
both P-glycoprotein and CYP3A in vitro. Drug Metab Dispos. 2000;28:895-898.
FREE FULL TEXT
44. Abernethy DR, Flockhart DA. Molecular basis of cardiovascular drug metabolism: implications for
predicting clinically important drug interactions. Circulation. 2000;101:1749-1753.
FREE FULL TEXT
45. Tracy TS, Korzekwa KR, Gonzalez FJ, Wainer IW. Cytochrome P450 isoforms involved in metabolism of the enantiomers
of verapamil and norverapamil. Br J Clin Pharmacol. 1999;47:545-552.
FULL TEXT
|
ISI
| PUBMED
46. Fromm MF, Dilger K, Busse D, Kroemer HK, Eichelbaum M, Klotz U. Gut wall metabolism of verapamil in older people: effects of rifampicin-mediated
enzyme induction. Br J Clin Pharmacol. 1998;45:247-255.
FULL TEXT
|
ISI
| PUBMED
47. Fromm MF, Busse D, Kroemer HK, Eichelbaum M. Differential induction of prehepatic and hepatic metabolism of verapamil
by rifampin. Hepatology. 1996;24:796-801.
FULL TEXT
|
ISI
| PUBMED
48. Barbarash RA, Bauman JL, Fischer JH, Kondos GT, Batenhorst RL. Near-total reduction in verapamil bioavailability by rifampin: electrocardiographic
correlates. Chest. 1988;94:954-959.
FREE FULL TEXT
49. Holtbecker N, Fromm MF, Kroemer HK, Ohnhaus EE, Heidemann H. The nifedipine-rifampin interaction: evidence for induction of gut
wall metabolism. Drug Metab Dispos. 1996;24:1121-1123.
ABSTRACT
50. Heinig R. Clinical pharmacokinetics of nisoldipine coat-core. Clin Pharmacokinet. 1998;35:191-208.
FULL TEXT
|
ISI
| PUBMED
51. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance
of cytochrome P450 3A4 inhibition. Clin Pharmacokinet. 2000;38:41-57.
FULL TEXT
|
ISI
| PUBMED
52. Sandstrom R, Knutson TW, Knutson L, Jansson B, Lennernas H. The effect of ketoconazole on the jejunal permeability and CYP3A metabolism
of (R/S)-verapamil in humans. Br J Clin Pharmacol. 1999;48:180-189.
FULL TEXT
|
ISI
| PUBMED
53. Jalava KM, Olkkola KT, Neuvonen PJ. Itraconazole greatly increases plasma concentrations and effects of
felodipine. Clin Pharmacol Ther. 1997;61:410-415.
FULL TEXT
|
ISI
| PUBMED
54. Koley AP, Robinson RC, Markowitz A, Friedman FK. Drug-drug interactions: effect of quinidine on nifedipine binding to
human cytochrome P450 3A4. Biochem Pharmacol. 1997;53:455-460.
FULL TEXT
|
ISI
| PUBMED
55. Smith SR, Kendall MJ, Lobo J, Beerahee A, Jack DB, Wilkins MR. Ranitidine and cimetidine drug interactions with single dose and steady-state
nifedipine administration. Br J Clin Pharmacol. 1987;23:311-315.
ISI
| PUBMED
56. Schwartz JB, Upton RA, Lin ET, Williams RL, Benet LZ. Effect of cimetidine or ranitidine administration on nifedipine pharmacokinetics
and pharmacodynamics. Clin Pharmacol Ther. 1988;43:673-680.
ISI
| PUBMED
57. Lam YWF, Shepherd AMM. Drug interactions in hypertensive patients: pharmacokinetic, pharmacodynamic
and genetic considerations. Clin Pharmacokinet. 1990;18:295-317.
ISI
| PUBMED
58. Katoh M, Nakajima M, Shimada N, Yamazaki H, Yokoi T. Inhibition of human cytochrome P450 enzymes by 1,4-dihydropyridine
calcium antagonists: prediction of in vivo drug-drug interactions. Eur J Clin Pharmacol. 2000;55:843-852.
FULL TEXT
|
ISI
| PUBMED
59. Upton RA. Pharmacokinetic interactions between theophylline and other medication
(part I). Clin Pharmacokinet. 1991;20:66-80.
ISI
| PUBMED
60. Chiu SHL. The use of in vitro metabolism studies in the understanding of new
drugs. J Pharmacol Toxicol Methods. 1993;29:77-83.
FULL TEXT
|
ISI
| PUBMED
61. Jones TE, Morris RG, Mathew TH. Diltiazem-cyclosporin pharmacokinetic interaction: dose-response relationship. Br J Clin Pharmacol. 1997;44:499-504.
FULL TEXT
|
ISI
| PUBMED
62. Campana C, Regazzi MB, Buggia I, Molinaro M. Clinically significant drug interactions with cyclosporin: an update. Clin Pharmacokinet. 1996;30:141-179.
ISI
| PUBMED
63. Kantola T, Kivisto KT, Neuvonen PJ. Erythromycin and verapamil considerably increase serum simvastatin
and simvastatin acid concentrations. Clin Pharmacol Ther. 1998;64:177-182.
FULL TEXT
|
ISI
| PUBMED
64. Gruer PJ, Vega JM, Mercuri MF, Dobrinska MR, Tobert JA. Concomitant use of cytochrome P450 3A4 inhibitors and simvastatin. Am J Cardiol. 1999;84:811-815.
FULL TEXT
|
ISI
| PUBMED
65. Varhe A, Olkkola KT, Neuvonen PJ. Diltiazem enhances the effects of triazolam by inhibiting its metabolism. Clin Pharmacol Ther. 1996;59:369-375.
FULL TEXT
|
ISI
| PUBMED
66. Ahonen J, Olkkola KT, Salmenpera M, Hynynen M, Neuvonen PJ. Effect of diltiazem on midazolam and alfentanil disposition in patients
undergoing coronary artery bypass grafting. Anesthesiology. 1996;85:1246-1252.
FULL TEXT
|
ISI
| PUBMED
67. Varis T, Backman JT, Kivisto KT, Neuvonen PJ. Diltiazem and mibefradil increase the plasma concentrations and greatly
enhance the adrenal-suppressant effect of oral methylprednisolone. Clin Pharmacol Ther. 2000;67:215-221.
FULL TEXT
|
ISI
| PUBMED
68. Backman JT, Wang JS, Wen X, Kivisto KT, Neuvonen PJ. Mibefradil but not isradipine substantially elevates the plasma concentrations
of the CYP3A4 substrate triazolam. Clin Pharmacol Ther. 1999;66:401-407.
FULL TEXT
|
ISI
| PUBMED
69. Lamberg TS, Kivistö KT, Neuvonen PJ. Effects of verapamil and diltiazem on the pharmacokinetics and pharmacodynamics
of buspirone. Clin Pharmacol Ther. 1998;63:640-645.
FULL TEXT
|
ISI
| PUBMED
70. Lown KS, Bailey DG, Fontana RJ, et al. Grapefruit juice increases felodipine oral availability in humans by
decreasing intestinal CYP3A protein expression. J Clin Invest. 1997;99:2545-2553.
ISI
| PUBMED
71. Soons PA, Vogels BA, Roosemalen MC, et al. Grapefruit juice and cimetidine inhibit stereoselective metabolism
of nitrendipine in humans. Clin Pharmacol Ther. 1991;50:394-403.
ISI
| PUBMED
72. Takanaga H, Ohnishi A, Murakami H, et al. Relationship between time after intake of grapefruit juice and the
effect on pharmacokinetics and pharmacodynamics of nisoldipine in healthy
subjects. Clin Pharmacol Ther. 2000;67:201-214.
FULL TEXT
|
ISI
| PUBMED
73. Fuhr U. Drug interactions with grapefruit juice: extent, probable mechanism
and clinical relevance. Drug Saf. 1998;18:251-272.
FULL TEXT
|
ISI
| PUBMED
74. Dresser GK, Bailey DG, Carruthers SG. Grapefruit juice: felodipine interaction in the elderly. Clin Pharmacol Ther. 2000;68:28-34.
FULL TEXT
|
ISI
| PUBMED
75. Rashid TJ, Martin U, Clarke H, Waller DG, Renwick AG, George CF. Factors affecting the absolute bioavailability of nifedipine. Br J Clin Pharmacol. 1995;40:51-58.
ISI
| PUBMED
76. Jurima-Romet M, Huang HS. Comparative cytotoxicity of angiotensin-converting enzyme inhibitors
in cultured rat hepatocytes. Biochem Pharmacol. 1993;46:2163-2170.
FULL TEXT
|
ISI
| PUBMED
77. Stearns RA, Chakravarty PK, Chen R, Chiu SHL. Biotransformation of losartan to its active carboxylic acid metabolite
in human liver microsomes: role of cytochrome P4502C and 3A subfamily members. Drug Metab Dispos. 1995;23:207-215.
ABSTRACT
78. Williamson KM, Patterson JH, McQueen RH, Adams KF Jr, Pieper JA. Effects of erythromycin or rifampin on losartan pharmacokinetics in
healthy volunteers. Clin Pharmacol Ther. 1998;63:316-323.
FULL TEXT
|
ISI
| PUBMED
79. Kazierad DJ, Martin DE, Blum RA, et al. Effect of fluconazole on the pharmacokinetics of eprosartan and losartan
in healthy male volunteers. Clin Pharmacol Ther. 1997;62:417-425.
FULL TEXT
|
ISI
| PUBMED
80. Bourrié M, Meunier V, Berger Y, Fabre G. Role of cytochrome P-4502C9 in irbesartan oxidation by human liver
microsomes. Drug Metab Dispos. 1999;27:288-296.
FREE FULL TEXT
81. Taavitsainen P, Kiukaanniemi K, Pelkonen O. In vitro inhibition screening of human hepatic P450 enzymes by five
angiotensin-II receptor antagonists. Eur J Clin Pharmacol. 2000;56:135-140.
FULL TEXT
|
ISI
| PUBMED
82. Schmidt EK, Antonin KH, Flesch G, Racine-Poon A. An interaction study with cimetidine and the new angiotensin II antagonist
valsartan. Eur J Clin Pharmacol. 1998;53:451-458.
FULL TEXT
|
ISI
| PUBMED
83. Dina R, Jafari M. Angiotensin II-receptor antagonists: an overview. Am J Health Syst Pharm. 2000;57:1231-1241.
FREE FULL TEXT
84. Flockhart DA. Drug interactions, cardiac toxicity, and terfenadine: from bench to
clinic? [editorial] J Clin Psychopharmacol. 1996;16:101-103.
FULL TEXT
|
ISI
| PUBMED
85. Vestal RE, Gurwitz JH. Geriatric pharmacology. In: Carruthers SG, Hoffman BB, Melmon KL, Nierenberg DW, eds. Melmon and Morrelli's Clinical Pharmacology Basic Principles in
Therapeutics. 4th ed. New York, NY: McGraw-Hill Health Professions
Division; 2000:1151-1177.
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