The recent withdrawal of the calcium antagonist mibefradil

Transcription

1 Cardiovascular Drugs Molecular Basis of Cardiovascular Drug Metabolism Implications for Predicting Clinically Important Drug Interactions Darrell R. Abernethy, MD, PhD; David A. Flockhart, MD, PhD 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 Cytochrome P-450 Associated Interactions Major improvements in the scientific tools available to study cytochrome P-450 (CYP) mediated biotransformations over the past decade 4 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 CYPbased 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 dml.georgetown.edu/depts/pharmacology/davetab.html. 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) 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 anticoagulation 14 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 -adrenoceptor blocking activity. Because formation of 5-hydroxypropafenone is via CYP2D6, patients who have genetically deficient 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 abernethyd@grc.nia.nih.gov (Circulation. 2000;101: ) 2000 American Heart Association, Inc. Circulation is available at

2 1750 Circulation April 11, 2000 TABLE 1. Some Clinically Important Cardiovascular Drug Interactions Inhibitory interactions (substrate/inhibitor) Inducing interactions (substrate/inducer) Theophylline/ ciprofloxacin Specific CYP Enzyme 1A2 2C19 2C9 3A Theophylline/ cigarette smoking Phenytoin/ omeprazole Warfarin/amiodarone HMG-CoA reductase inhibitors (except pravistatin)/ erythromycin, clarithromycin Phenytoin/ticlopidine Warfarin/fluconazole Cyclosporine, tacrolimus/ verapamil, diltiazem Cisapride/ketoconazole, itraconazole Phenytoin/rifampin Warfarin/ barbiturates A comprehensive listing can be found at Cyclosporine, tacrolimus/ rifampin CYP2D6 activity exhibit markedly greater -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 CYP2D 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 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. P-Glycoprotein Drug Transport and Drug Interactions 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 al 35 have been able to establish the mechanism for TABLE 2. Ethnic Variation in CYP Polymorphic Drug Metabolism CYP2D6, % CYP2C19, % CYP2C9, % Absent Present Ultrarapid Absent Present Absent Present African/African-American 8 92? Asian White

3 Abernethy and Flockhart Molecular Basis of CV Drug Metabolism 1751 TABLE 3. Drugs That May Interact With P-Glycoprotein at Therapeutic Doses Cardiovascular Anticancer Other Antiarrhythmics Phenothiazines Amiodarone 34 Vinblastine 46 Chlorpromazine 34 Quinidine 34 Vincristine 46 Fluphenazine 34 Propafenone 34 Doxorubicin 46 Promethazine 34 Calcium antagonists Daunorubicin 46 Trifluoperazine 34 Verapamil 43 Epirubicin 46 Trifluopromazine 34 Diltiazem 44 Idarubicin 46 Paclitaxel 46 Digoxin 35 Docetaxel 46 Pimozide 34 Dipyridamole 34 Etoposide 46 Terfenadine 47 Reserpine 45 Teniposide 46 Ivermectin 48 Spironolactone 34 Mitoxantrone 46 Ketoconazole 36 Dactinomycin 46 Itraconazole 31 Amsacrine 46 Mefloquine 49 Trimetrexate 46 Erythromycin 50 Topotecan 46 Clarithromycin 37 Mithramycin 46 Levofloxacin 31 Mitomycin c 46 Tamoxifen 46 HIV protease inhibitors Indinavir 33 Nelfinavir 33 Saquinavir 33 Immunosuppressives Cyclosporine 51 Tacrolimus 52 Domperidone 53 Loperamide 53 Ondansetron 53 the digoxin-quinidine clinical interaction as that of quinidinemediated 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. Discussion 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

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