There is no guide, chart, or computer software program for clinicians to clearly identify or quickly predict which drugs interact with the CYP enzymes and create clinically significant drug interactions in patients. More research and clinical drug trials need to be conducted and reported on these enzymes and their interactions. With the knowledge of how cytochrome P450 enzymes enzymes work and of their physiologic role in DIs, pharmacists can better predict significant interactions that are likely to occur or identify potentially problematic drugs.

Understanding which P450 isozyme is responsible for the metabolism of a drug will be essential when trying to predict and understand the magnitude of drug interactions. Some drug metabolism inhibitors are highly selective for certain CYP isozymes. Some drugs that are highly selective enzyme inhibitors may also be substrates for that same enzyme system and may cause an interaction by being a competitive inhibitor. Obviously, if it is known that a new drug is metabolized by a specific CYP isozyme system, it is logical to assume that the drug will exhibit DIs with known inducers and inhibitors of specific CYP isozyme(s).

Drugs having the highest capability for producing life-threatening or serious clinical consequences include those with a narrow therapeutic index. These drugs include warfarin, carbamazepine, lithium, procainamide, phenytoin, quinidine, theophylline, tricyclic antidepressants, and valproic acid, and/or highly protein bound agents such as warfarin, phenytoin, oral hypoglycemic agents, sulfonamides, and NSAIDs that may be substrates, inhibitors and/or inducers of either CYP1A2, CYP2C9, CYP2C19, CYP2D6, and/or CYP3A4 isozymes. Management of patients in a clinical setting can be simplified if drugs that are known to produce harmful DIs with each other are avoided or limited and the patient is closely monitored by a clinical pharmacist and/or physician.

If a drug interaction is suspected, the following approach may be helpful in determining the offending agents. First, determine that the drug interaction is not related to poor patient compliance or improper dosing of a drug. Second, determine if genetic polymorphism could be involved. Third, determine what new drugs have been recently added to or discontinued from the patient’s regimen and if the adverse effect seen is commonly associated with the new drug or any drug the patient routinely receives. Fourth, determine how each drug the patient receives is metabolized or eliminated from the body. Fifth, determine if any drug the patient receives is a substrate, inhibitor or inducer of any CYP isozymes. Lastly, after reflecting on the adverse effects the patient is experiencing, determine if these are commonly associated with any of the drugs. Consulting Tables 1–4 in this article can help identify possible interacting drugs. After the problem is identified, the drug(s) should be quickly replaced with an alternative drug not likely to produce the adverse effects.

The CYP2C subfamily consists of 2C9, 2C10, and 2C19 isozymes as well as others. While these enzymes metabolize a smaller number of drugs, many of these drugs are involved in clinically significant DIs. Drugs that are substrates for CYP2C isoenzymes include nonsteroidal anti-inflammatory drugs (NSAIDs) [2C9], phenytoin (2C9), S-warfarin (2C9), amiodarone (2C9), omeprazole and lansoprazole (2C19), and diazepam, clomipramine, amitriptyline and imipramine (2C). Common drugs that are potent inhibitors of 2C9 enzymes include amiodarone, fluvastatin, fluconazole, and omeprazole (2C19), etc. Genetic polymorphism plays a major role with the CYP2C subfamily. Drugs involved with CYP2C are listed in Table 4.

How These Enzymes Modulate Drug–Drug Interactions: Drug interactions can occur when CYP enzymes are either inhibited or induced by certain drugs. Drugs can either significantly enhance or diminish the pharmacologic activity of CYP enzymes.Induction of the gene responsible for producing the enzyme increases the rate of production of the enzyme, thus increasing the cellular content and activity of the induced CYP enzymes. Since enzyme induction involves protein synthesis, there is generally a time delay in both the onset and offset relative to starting and stopping the inducing agent. Therefore, the full effect of the inducing agent may not be evident for several weeks after the inducer drug has been started. The resulting effect will take a similar period of time to fully dissipate after the agent has been discontinued and the rate of enzyme production returns to baseline.

Drug-induced inhibition of CYP enzymes is usually due to competitive binding at enzyme-binding sites and generally occurs within a few hours.The magnitude of inhibition is a function of the concentration of the inhibiting agent. Thus, the half-life of the inhibitor drug will determine how long it must be administered before the full inhibition effect on CYP enzymes is achieved and, conversely, how long after its discontinuation the inhibition phase will endure.

Drug–drug interactions involving CYP isozymes can be either pharmacodynamic or pharmacokinetic in nature. Pharmacodynamic interactions can occur when the mechanism of action of one drug enhances or diminishes the effect produced by the mechanism(s) of action of another drug. Pharmacokinetic interactions can occur when the effect of one drug alters the pharmacokinetic action (e.g., absorption, distribution, metabolism and/or excretion/elimination) of another, leading to a change in its effective concentration at its site(s) of action.

A large number of drug interactions are concentration-dependent, with the risk of the DI increasing with increased plasma levels of these drugs. In patients who receive medications that have a very long elimination half-life (e.g., antidepressants), the time required for the drug to reach steady-state plasma levels can be quite long. This can affect the time course for the onset of clinically significant drug interactions. Using fluoxetine as an example, when taken routinely, it would take approximately one month for it to reach a steady-state level in the bloodstream and cause a drug interaction. Drugs with long half-lives are also generally very slowly metabolized in the body. Consequently, the risk of drug interactions with these drugs may persist for a long period of time after the drug is discontinued. For example, the risk for drug interactions with fluoxetine should be considered for up to six weeks after treatment has been withdrawn. In contrast, venlafaxine has a relatively short half-life of 5–11 hours, it takes 3–5 days to reach a steady-state level, and it may be associated with clinical drug interactions soon after treatment is initiated. In addition, some drugs have nonlinear kinetics, (e.g., fluoxetine and paroxetine), meaning that their concentrations increase to a greater extent than the increase in the parent drug would predict. Because drug interactions are concentration-dependent, higher doses of these medications confer greater risk than might be expected from studies with lower doses. In some instances the metabolite of the parent compound has a greater inhibitory effect on the metabolizing CYP isozyme(s). Thus, the potential for drug interactions may be greater in clinical practice where patients receive doses that are titrated to reach steady state or where they may receive higher initial doses.

Approximately 15% of all drugs used today are metabolized by the CYP1A2 isozyme. It is generally believed that there is no genetic polymorphism involved with this isozyme. Common drugs that are substrates for the CYP1A2 isozyme include
R-warfarin, theophylline, caffeine, and some benzodiazepines, antidepressants and antipsychotics. Although few in number, these drugs are commonly involved with a large number of clinically significant DIs. The most significant inhibitors of CYP1A2 include selected fluoroquinolones and fluvoxamine. Smoke (polycyclic aromatic hydrocarbons from cigarettes and charbroiled food), omeprazole, phenobarbital, phenytoin. rifampin and ritonavir are inducers of CYP1A2. Cruciferous vegetables (e.g., broccoli, cauliflower) can also induce this enzyme. Other drugs involved with CYP1A2 are listed in Table 3.

About 25% of all drugs used today are substrates for the CYP2D6 isozyme. This isozyme has been studied extensively. It greatly exhibits genetic polymorphism; certain individuals will lack this enzyme from birth as a result of an autosomal recessive defect in its expression. Individuals lacking CYP2D6 will have a much larger pharmacologic response to usual doses of drugs metabolized by this enzyme and will have a greater risk of adverse drug effects and/or toxicity. Conversely, prodrugs are usually inactive until enzymatic metabolism converts them to an active metabolite. Individuals will have little or no pharmacologic response to these drugs. CYP2D6 substrates include some tricyclic antidepressants, neuroleptics, antiarrhythmics, and b-adrenergic blockers. Inhibitors of CYP2D6 include tricyclics and SSRIs, and antiarrhythmics (particularly quinidine) and fluoxetine. CYP2D6 inducers include only a few drugs, primarily anticonvulsant agents. A more extensive listing of drugs involved with the CYP2D6 isoenzyme is shown in Table 2.

The CYP3A enzyme family is composed of four isozymes involved with metabolism: CYP3A, CYP3A4, CYP3A5, and CYP3A7. Of these, the CYP3A4 isozyme is the most common; however, these enzymes are so closely related, they are often referred to collectively by their subfamily name, CYP3A. The CYP3A enzyme family is responsible for hepatic metabolism of approximately 60% of currently available pharmaceutical agents.A significant quantity of CYP3A4 isozyme is present in the intestinal mucosa, especially in the duodenum, jejunum and, to a lesser extent, in the ileum. This isozyme is responsible for a majority of the first-pass metabolism of compounds. Common substrates for CYP3A4 include steroids, some tricyclic antidepressants, antifungals, benzodiazepines, calcium-channel blockers, hormones, macrolides, selective serotonin reuptake inhibitors (SSRIs), R-warfarin, etc. Inhibitors of CYP3A4 include some antifungals (e.g., azoles), antivirals (e.g., protease inhibitors), anticonvulsants, HMG-CoA reductase inhibitors (e.g., statins), macrolides, and verapamil. Inducers of CYP3A4 include glucocorticoids, rifampins, and some anticonvulsants. A comprehensive listing of drugs involved with CYP3A4 are listed in Table 1. To date, no data have been reported that suggest 3A4 isoenzymes exhibit genetic polymorphism.

Some drug metabolism by the CYP3A4 isozyme in the intestinal tract can be inhibited by ingesting grapefruit juice, which contains bioflavonoids (e.g., quercetin, kaempferol, and naringenin). Some calcium-channel modulators (e.g., nitrendipine, nifedipine, and felodipine) and other drugs metabolized by CYP3A4 may be affected. In one study the AUC for felodipine was increased two-to-three fold following oral administration along with grapefruit juice. The metabolism of buspirone, cyclosporine, terfenadine, midazolam, warfarin and caffeine can also be inhibited by grapefruit juice.

These CYP enzymes are present in every cell and are responsible for metabolizing or detoxifying consumed foreign (i.e., xeno) biological substances (e.g., toxins, carcinogens, mutagens and drugs). The enzymes primarily involved in drug metabolism are located in the liver. About 30 of these enzymes — especially the CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 isozymes — are primarily located in endoplasmic reticulum of hepatocytes in the liver and in the small intestine, with smaller quantities in the kidneys, lungs and brain.These enzymes play a major role in the metabolism of most drugs commonly used today. The CYP2E1 isozyme is more involved with inactivation of toxins than with drug metabolism.

The specific CYP isozyme responsible for the metabolism of many drugs, especially those marketed before 1980, is generally unknown. However, most if not all newer drugs have been identified in clinical trials as substrates, inducers, and/or inhibitors of certain CYP enzymes. A drug that inhibits a specific CYP isozyme may decrease the metabolism of the drug and increase serum concentrations of drugs that are substrates for that isoenzyme. Conversely, a drug that induces a specific CYP isozyme may increase the metabolism of the drug and decrease serum concentrations of drugs that are substrates for that isozyme. In general, the extent of CYP isozyme induction or inhibition increases significantly as the dose of the drug increases and/or duration of treatment increases.Pharmaceuticals in the same chemical class may vary quantitatively on their affinity for specific CYP enzymes. Some drugs are substrates for multiple CYP isozymes. Some drugs are racemic mixtures of stereoisomers and may be substrates for different isozymes and have varying affinity for the isozymes. The CYP family enzyme, its subfamily, and the individual enzyme are involved with metabolism of a drug, but the drug will be primarily metabolized by one specific enzyme.

Although pharmaceutical manufacturers may include in a drug monograph that drug “A” is a substrate for a CYP isozyme, the extent of its metabolism may not be known. In some instances, the degree to which a drug is metabolized by an isozyme may only be minimal, about 10%, or it may be extensively metabolized. Metabolism of the remaining drug will be modulated by other biochemical processes. The CYP enzymes are involved in converting pharmacologically active lipid-soluble compounds into usually inactive polar compounds, primarily through Phase I, oxidation, demethylation and hydroxlylation reactions.

Overall drug metabolism in the liver mediated by CYP enzymes is generally depressed during the first month post-transplantation, but recovers during the next few months. Interestingly, CYP2D6 appears to be unaffected by transplantation, while the activity of CYP2E1 enzyme is enhanced during the first month in liver transplant patients. Unless there is major liver damage or abuse, the CYP system’s activity generally remains at least adequate throughout life. Although liver function tests (e.g., AST, ALT) may be modestly elevated, there does not seem to a corresponding decrease in CYP enzyme metabolism.

The kidneys are usually known for their ability to excrete water, electrolytes, drugs and other chemicals. However, they are very active in the biotransformation of a variety of drugs. The CYP enzyme system in the kidneys has been identified as being as active as that in the liver, when corrected for organ mass. In patients with chronic renal failure, overall hepatic enzyme metabolism is decreased by anywhere from 26% to 71%. In vitro studies have demonstrated impaired function of CYP3A4 and 2C9 isozymes, whereas 1A2, 2C19 and 2D6 were not affected. Reversible drug metabolism may be affected by chronic renal disease when normal enzyme function is disrupted. The accumulation of uremic toxins has also been associated with a decreased CYP activity. Therefore, patients with severe renal insufficiency receiving chronic drug therapy may experience accumulation of metabolites of some agents as well as the parent compounds.

Genetic polymorphism plays a major role modulating drug interactions with the CYP metabolic enzyme system,and contributes to the classification of an individual as either a “poor metabolizer” or an “extensive metabolizer.” Poor metabolizers probably lack a gene for certain isozymes and cannot metabolize certain drug substrates well while extensive metabolizers have the appropriate gene for the isozyme and metabolize drugs normally. Poor metabolizers may achieve toxic serum drug concentrations when usual doses of certain drugs are prescribed for them, or, if the active drug moiety is a metabolite, they may not achieve the desired pharmacologic effect from the drug. They constitute a minority of the population.

The ethnic background of a patient can influence the likelihood that he or she will be a poor or extensive metabolizer. The incidence of individuals classified as poor metabolizers for the metabolic isozyme CYP2D6 is about 8% for Caucasians, 4% for African-Americans and <1% for Asians. This information is very important for clinicians because individuals with a CYP2D6 deficiency cannot convert the drug codeine to its active metabolite. These individuals will receive little if any analgesic benefit from taking codeine. Also, they will be unable to metabolize many of the psychotropic drugs — especially phenothiazines — and may experience toxicity when taking usual doses of these drugs. The incidence of poor metabolizers varies for other isoenzymes. For CYP2C19, approximately 5% of Caucasians and 20% of Asians and African-Americans are poor metabolizers. The CYP2C9 isozyme greatly exhibits genetic polymorphism and will be lacking in > or =20% of Caucasians and 2% of Asians and African-Americans.

CYP Nomenclature

Based on the current nomenclature established by Nebert et al., in 1987, the CYP enzymes represent a superfamily consisting of enzyme families designated by an Arabic or Roman numeral, (e.g., CYP3 or CYPIII). Subfamilies are designated by a capital letter (e.g., CYP3A or CYPIIIA), according to the similarity of amino acid sequences of the encoded CYP isoenzymes. The individual gene is designated by an Arabic number (e.g., CYP2C9 or CYPIIC9). This means that a CYP2C9 enzyme is closely related to CYP2C19 (same family and subfamily), somewhat related to CYP2D6 (same family), but not closely related to CYP1A2 (different family). Although the enzymes are somewhat related and share some general characteristics, each is unique and performs a distinct role.

Epidemiologists report that individuals older than 65 years of age have up to three times as many drug interactions as younger patients. This increased rate involves a number of factors, including age-related changes in physiology, receptor sensitivity, metabolic capacity, and the practice of polymedicine in this population. (However, clinical studies report that increasing age as a factor influencing drug interactions may involve other isozymes but has little impact on CYP3A4 catalytic activity.)

A patient case study and pharmaceutical care plan are included. The case study illustrates one or more drug interactions and offers the pharmacist an opportunity to identify drug interactions and develop a pharmaceutical care plan to address specific drug interaction problems. Since there are often numerous ways to resolve a problem, the pharmaceutical care plan included is one attempt at addressing the patient’s drug interaction problem(s).

One of the most important causes of preventable drug therapy problems is drug interactions (DIs). Factors contributing to DIs can be easily identified but preventing drug interactions is by far more difficult. To illustrate the quandary in which pharmacists find themselves and the complexity involved in evaluating drug interactions to determine safe drug use, the drug interaction portion of a drug monograph for a newly approved drug in the U.S. is reproduced below.

“Cevatine (name changed from original) should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with cevatine can be expected to have additive effects. Cevatine might interfere with desirable antimuscarinic effects of drugs used concomitantly. Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevatine. It should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at higher risk of adverse events. In an in vitro study, cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4 were not inhibited by exposure to cevatine.”

If cevatine were prescribed for a patient and you were the pharmacist involved, how would you approach determining whether or not it interacts with any of the other routine medication the patient takes? If the drug cevatine is not listed in your pharmacy’s computer drug information or drug interaction software programs, what drug information resources would you use? How would you advise a physician who asks, “Does cevatine interact with any other medication?” What strategies would you utilize to adequately prepare yourself to provide clinical information about drug interactions with cevatine?

With the increasing number of newer, complex drug compounds being developed, pharmacists, as the most readily accessible healthcare providers, are asked to bear much of the burden for detecting and preventing potentially serious drug interactions. Unfortunately, few pharmacists (and even fewer physicians) have received extensive training on the CYP metabolic enzyme system. As a result, many pharmacists primarily rely on computer software programs and/or drug information handbooks to detect drug interactions and provide an appropriate course of action to resolve them. However, given the rapid pace at which new drugs are introduced and new drug interactions are reported, these information resources rapidly become outdated, placing both patients and practitioners at risk.

National concern about drug interactions with CYP enzymes heightened in the 1990s when fatal cardiac arrhythmias were suspected with the interactions of terfenadine with erythromycin and ketoconazole.Ultimately terfenadine was withdrawn from the U.S. market. Since then, more examples of serious DIs involving CYP enzymes have been reported and the medical community has become very cautious about starting patients on new drugs that are metabolized by the CYP enzyme system. For example, the recent withdrawal of mibefradil from the U.S. market was, in part, due to its high potential to inhibit certain CYP enzymes and cause harmful drug interactions. Another example is the recently revised warnings in product labeling of the drug cisapride due to its risk of causing potentially fatal cardiac arrhythmias when combined with certain CYP enzyme inhibitors. As knowledge of the CYP enzyme system and reports of its involvement in potentially lethal DIs continue to increase, practitioners, researchers and pharmaceutical manufacturers have become concerned. The following overview of the CYP enzyme system is designed to help pharmacists become more knowledgeable about its ability to cause significant drug interactions.

The Cytochrome P450 Enzyme System

The term “cytochrome P450″ refers to a family of over 100 enzymes in the human body that modulate various physiologic functions. Although knowledge of these enzymes and their mechanism of action is growing, much about their physiologic role and function remains unknown. These enzymes were first identified in the 1950s to 1960, but specific research on them did not begin until the 1970s. Identification of their specific CYP genes using DNA cloning techniques did not begin until the mid-1980s. The first gene to be coded for a specific CYP enzyme occurred around 1990. The CYP enzyme system contains two large subgroups: steroidogenic and xenobiotic enzymes. The steroidogenic group is not involved in the metabolism of drugs. The xenobiotic group includes four major enzyme families: CYP1, CYP2, CYP3, and CYP4. These enzymes perform a number of physiologic functions but their primary role involves the metabolism of drugs.

The presence of these enzymes and their function are genetically determined. They enable humans to metabolize plant toxins and related toxic substances before the substances enter the systemic circulation and cause cell damage. Since many drugs are derived from botanical compounds and may resemble plant toxins, they are metabolized by these enzymes and at times by other biotransformation processes. Initially, a drug will have one principal CYP enzyme responsible for its metabolism, but if the drug concentration reaches a sufficient level in the body, a second enzyme will be released to continue the metabolic process. If needed, a third and fourth enzyme can become activated to complete biotransformation of a drug or substance into a polar metabolite that can be eliminated from the body in urine or feces.