(Circulation. 2000;101:1749.)
© 2000 American Heart Association, Inc.
Cardiovascular Drugs |
Molecular Basis of Cardiovascular Drug Metabolism
Implications for Predicting Clinically Important Drug Interactions
From the Division of Clinical Pharmacology, Georgetown University Medical Center, Washington, DC.
Correspondence to Darrell R. Abernethy, MD, PhD, Laboratory for Clinical Investigation, National Institute on Aging, Gerontology Research Center, 5600 Nathan Shock Dr, Baltimore, MD 21224-6825. E-mail abernethyd{at}grc.nia.nih.gov
Key Words: drugs • metabolism • molecular biology
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Introduction |
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 Top Introduction Cytochrome P-450-Associated...P-Glycoprotein Drug Transport...DiscussionReferences |
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The recent withdrawal of the calcium antagonist mibefradil from the market in the United States has refocused attention on drug interactions that involve cardiovascular drugs.1 It is appropriate to ask whether pharmacokinetic drug interactions like this that pose substantial clinical risk can be predicted and/or prevented. We believe that if the appropriate information is obtained during drug development and effectively communicated to physicians, many episodes such as that involving mibefradil will be predicted and prevented.
Many known pharmacokinetic drug interactions with the potential for either excessive drug exposure, effect, and toxicity or decreased drug exposure and loss of drug effect are associated with phase I drug biotransformations.2 In addition, the importance of P-glycoprotein–mediated drug transport is currently being appreciated.3
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Cytochrome P-450–Associated Interactions |
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TopIntroductionCytochrome P-450-Associated...P-Glycoprotein Drug Transport...DiscussionReferences |
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Major improvements in the scientific tools available to study cytochrome P-450 (CYP)–mediated biotransformations over the past decade4 now permit prediction of potential drug interactions during drug development. In some cases, these tools can be used to determine which of a series of drug candidates should undergo clinical development. They can also be used to understand and identify interactions between drugs that are in clinical use. An important component of this understanding is the challenge to determine the patient risk associated with each potential drug interaction because many pharmacokinetic drug interactions have no meaningful clinical consequence.5
The CYP family of enzymes, located in the liver and gastrointestinal tract, is the major source of catalytic activity for drug oxidation in humans.6 This enzyme family consists of >30 isoforms, but only a few have importance in human drug metabolism. This immensely simplifies the understanding of the system for prescribers. Briefly, naming of the CYP enzymes includes designation of the family, subfamily, and gene so that CYP 1(family), A(subfamily), 2(gene) designates the CYP isoform most associated with theophylline biotransformation.6 Therefore, drugs that inhibit CYP1A2 (eg, ciprofloxacin) are predicted to elevate plasma theophylline and produce toxicity,7 and exposures that induce CYP1A2 (eg, cigarette smoking) are predicted to reduce theophylline plasma concentrations.8 The possibility of CYP-based interactions can now be predicted from in vitro data obtained from human liver microsomes or recombinant preparations of pure CYP enzymes.4 However, in vitro studies can document only that an interaction between a drug or drugs and a CYP enzyme is possible; they cannot predict in vivo distribution or concentration of drug at its site of biotransformation at clinically used doses. Therefore, important predictions should always be tested for validity by confirmatory clinical studies. Predictions of inductive interactions are more difficult with in vitro methods; however, study of CYP enzyme induction in cultured human hepatocytes is an area of rapid progress.9 These in vitro studies must be done with human enzyme sources as enzymes expressed because enzyme substrate specificity obtained from any animal model do not extrapolate well to humans.10
The CYP isoforms known to be important for
cardiovascular drug biotransformation include CYP3A,
CYP2D6, CYP1A2, CYP2C19, and CYP2C9.4 Table 1
shows selected
inhibitory and inductive drug interactions. A more complete
listing of drugs that are substrates, inducers, and
inhibitors of the CYP isoforms can be found on the web at
http://www. dml.georgetown.edu/depts/pharmacology/davetab.html.
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CYP3A and CYP1A2 have highly variable expression across the
population, even in the absence of concurrent ingestion of an
inhibiting or inducing drug. The population distribution of these
enzymatic activities (and therefore clearance of drugs that are
metabolized by these enzymes) is continuous, with most individuals
having an intermediate level of activity and some individuals having
very low or very high activity. In contrast, CYP2C19, CYP2C9, and
CYP2D6 activities are significantly influenced by genetic
polymorphisms that occur with frequencies that vary among different
ethnic groups (Table 2).11 12 13 14 The clinical
consequence of such polymorphisms can be profound. For example,
individuals with genetically determined defects in CYP2C9 activity have
been reported to require 0.5 mg/d warfarin for adequate
anticoagulation14 because metabolic inactivation of
S-warfarin, the active enantiomer, is almost exclusively mediated by
CYP2C9.14 15 Another example is propafenone. In addition
to the antiarrhythmic properties of both propafenone and its
major metabolite and 5-hydroxypropafenone, propafenone has weak
ß-adrenoceptor blocking activity. Because formation of
5-hydroxypropafenone is via CYP2D6, patients who have genetically
deficient CYP2D6 activity exhibit markedly greater ß-adrenoceptor
blockade and central nervous system side effects than patients with
high CYP2D6 activity.16 17 Of note, the contribution of
CYP2D6 to drug elimination may be obscured if renal clearance is a
significant component of elimination kinetics. This is the case with
flecainide, for which the documented contribution of the genetic
polymorphism in CYP2D618 19 20 has no pharmacodynamic
relevance. Renal clearance of unchanged flecainide is a major pathway
in individuals with normal renal function. Therefore, only in patients
with markedly decreased renal function in whom flecainide
biotransformation by CYP2D6 is a major route of clearance would the
absence of CYP2D6 activity be associated with further impairment of
elimination compared with individuals with wild-type CYP2D6
activity.21
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The biotransformation of most drugs is not carried out by one specific CYP enzyme. Phenytoin biotransformation is catalyzed by both CYP2C19 and CYP2C9.22 23 Individuals with polymorphically decreased activity of either enzyme have higher serum phenytoin concentration at a given dose.24 25 The clinical impact of each individual enzyme is diluted, however, because the other enzyme contributes significantly to phenytoin biotransformation.26 The coincident presence of both 2C9 and 2C19 low-activity variants is extremely rare and has not been evaluated in clinical study.
The specificity and potency of the interaction of a drug with a particular CYP enzyme is also central to the definition of the clinical importance of potential inhibitory drug interactions. For example, the potent and specific CYP3A inhibitor itraconazole blocks the biotransformation of 2 drugs, astemizole and simvastatin, each of which is a very specific substrate for CYP3A. When itraconazole is coadministered with either of these drugs, the clinical result may be astemizole-induced torsade de pointes arrhythmia or simvastatin-induced rhabdomyolysis, respectively.27 28 In contrast, cimetidine, a less potent and less specific CYP3A inhibitor, is associated with neither of these potentially life-threatening drug interactions.
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P-Glycoprotein Drug Transport and Drug Interactions |
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TopIntroductionCytochrome P-450-Associated...P-Glycoprotein Drug Transport...DiscussionReferences |
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The role of P-glycoprotein as a drug transporter across cell membranes in cancer chemotherapy is well known,29 and its role in multiple drug resistance to anticancer drugs has been extensively characterized.30 Much more recently, with the development of the mdr-1 knockout transgenic mouse, it has become apparent that P-glycoprotein drug transport is much more general, with evidence that it serves as a renal drug transporter,31 as an efflux pump from the central nervous system for selected drugs,32 and in the intestinal wall as a barrier to drug absorption.33 In cardiovascular therapeutics, therapeutic doses of verapamil inhibit P-glycoprotein, and this, in addition to its inhibitory effect on CYP3A, contributes to a marked increase in cyclosporine absorption and availability when the drugs are coadministered. Both inhibition of intestinal CYP3A, limiting cyclosporine metabolism, and P-glycoprotein inhibition, limiting this barrier to absorption, are thought to contribute to this drug interaction. Conversely, cyclosporine, as a P-glycoprotein substrate, competitively inhibits verapamil-mediated P-glycoprotein inhibition.34 Examples of drugs currently identified as substrates or inhibitors of P-glycoprotein are shown in Table 3
. It is important to note that a variety
of methods, such as the mdr-1 knockout mouse and other in vitro and in
vivo techniques, were used to determine the effect of the listed drug
on P-glycoprotein; therefore, in many cases, clinical
studies will be needed to establish whether there is a clinical
correlate to the laboratory finding. In some cases, clinical studies
have already demonstrated an interaction and preclinical work has
defined P-glycoprotein as the likely site of the
interaction. For example, Fromm et al35 have been able to
establish the mechanism for the digoxin-quinidine clinical interaction
as that of quinidine-mediated inhibition of
P-glycoprotein–mediated digoxin transport. This clinical
interaction, with decreases in both digoxin volume of distribution and
digoxin clearance with quinidine coadministration, had previously been
without a satisfactory mechanistic explanation. Similarly, the marked
increase in digoxin bioavailability with macrolide antibiotic (eg,
erythromycin) coadministration had previously been attributed to
macrolide-induced change in gut flora. Although antibiotics may impair
gut digoxin metabolism, an alternative explanation now
appears to be that the macrolide antibiotic additionally inhibits both
intestinal P-glycoprotein–mediated inhibition of digoxin
absorption and renal elimination.36 37 A series of
well-designed clinical studies is required to establish the clinical
importance of this new type of drug interaction for the drugs listed in
Table 3.
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Discussion |
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TopIntroductionCytochrome P-450-Associated...P-Glycoprotein Drug Transport...DiscussionReferences |
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How does this information allow better prediction of potential pharmacokinetic drug interactions with cardiovascular drugs? In vitro study of the metabolism of a drug candidate or a new drug using tissue from human liver preparations and recombinant enzymes allows qualitative definition of the CYP isoforms involved in the biotransformation of the drug of interest. Similarly, in vitro cell systems that express P-glycoprotein can be used to screen for potential interactions. These same experimental systems allow evaluation of the inhibitory potential of other concurrently administered drugs. CYP enzyme inhibition may block biotransformation of the active drug to inactive metabolites, or as in the case of a drug such as losartan, it may block biotransformation of a less active precursor drug to the pharmacologically active metabolite.38 P-glycoprotein inhibition may alter the gastrointestinal absorption, renal clearance, or access to the central nervous system of concurrently administered P-glycoprotein substrates.
In the case of the mibefradil, in vitro and in vivo studies demonstrated that it inhibited both CYP3A and CYP2D6. There was no information about potential P-glycoprotein inhibition. Therefore, the potential for a toxic metabolic drug interaction with HMG CoA reductase inhibitors and nonsedating antihistamines such as astemizole should have been predicted and evaluated in a small, focused, and controlled clinical study. Without knowledge of the possibility of P-glycoprotein effects, no predictions could be made; however, a pharmacokinetic drug interaction with cyclosporine was reported, which raises the possibility of mibefradil effects on P-glycoprotein as well.39 Instead, only after the list of potentially toxic interactions with coadministered drugs was assembled by the FDA was the drug withdrawn.1 40 41
In the case of inductive drug interactions, in vitro evaluations are not as fully developed. Human hepatocyte cultures able to maintain the capacity for CYP enzyme induction are in development and may be useful in the future for predictive purposes.9 Currently, a focused clinical study remains the most useful tool to define a potential interaction involving CYP enzyme induction.
The methods described here for the study of CYP enzyme effects are in
routine use during development of cardiovascular drugs
by pharmaceutical companies. Assessment of the effect of
P-glycoprotein (and other drug transport molecules that are
only now being defined) is more preliminary, but we predict that such
evaluation will soon be routine during drug development. If our
collective experience with mibefradil is
representative, we are not yet taking full advantage of
these methods in drug development. For clinical practice, the
increasing availability of simple tables, such as Table 1
,
allows prediction of potential drug interactions when a drug is
concurrently administered with an inhibitor or inducer of
its CYP enzyme(s) of biotransformation. Similarly, the potential for
P-glycoprotein–mediated interactions can be inferred from
Table 3.
Of note, drug interactions are not always harmful, as in the case of inhibitory interactions between verapamil or diltiazem and cyclosporine that permit a lower dose of cyclosporine to be administered with equal therapeutic benefit but at lower cost.42
In summary, understanding and predicting potential drug interactions is now far from a purely empiric exercise. Currently, potential pharmacokinetic interactions of known cardiovascular drugs are often predictable, and as new drugs become available, the information needed for prediction should be part of the development program. This information can now be presented in an organized summary that provides prescribers with a simple and rapid means of checking for potential interactions.
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Acknowledgments |
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This work was supported in part by NIH grants AG-08226, GM-08386, and GM-56898. We are grateful to Anne Nguyen and Julita Nieve for assistance in manuscript preparation.
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References |
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