Clinically Significant Drug Interaction with the Cytochrome P450 Enzyme System
Many drugs undergo oxidative biotransformation in order to be transformed from lipophilic to hydrophilic compounds so that they may be more readily eliminated from the body. The cytochrome P450 enzyme system is the major catalyst of oxidative biotransformation reactions involved in drug metabolism. The nomenclature of the cytochrome P450 enzyme system involves grouping the enzymes into families and subfamilies. Of the different isoforms of cytochrome P450, CYP3A4 is the most prevalent in humans and is the most important form of the enzyme in terms of drug metabolism. The cytochrome P450 enzyme system plays a significant role in drug metabolism, particularly with regard to drug interactions. Many drug interactions are a result of inhibition or induction of the cytochrome P450 enzymes. In particular, the CYP3A4 isoenzyme is involved in many clinically significant drug interactions, including the well-documented seldane® (terfenadine) – erythromycin drug interaction which resulted in terfenadine being withdrawn from the market.
The nonsedating antihistamines and cisapride are also involved in drug interactions mediated by CYP3A4, resulting in cardiac arrhythmias that can be potentially fatal. The CYP3A4 and CYP1A2 isoenzymes are also involved in drug interactions with theophylline, potentially resulting in theophylline toxicity. The CYP2D6 isoenzyme is involved in the metabolism of many of the antidepressants (e.g., the Selective Serotonin Reuptake Inhibitors or SSRIs) such that the combination of the SSRIs with other psychotropic agents which are CYP2D6 substrates can lead to serious adverse effects or death due to toxic levels of the drug. Many of the drug interactions involving the cytochrome P450 enzyme system result in expensive hospitalizations to treat serious adverse drug reactions, or have fatal outcomes. By understanding the role of the cytochrome P450 enzyme system in drug metabolism, clinicians are better able to prevent clinically significant drug interactions having detrimental effects.
The Cytochrome P450 Enzyme System
The CYP450 enzyme system is a key pathway for drug metabolism. Many lipophilic drugs must undergo biotransformation to more hydrophilic compounds to be excreted from the body. Drug biotransformation reactions consist of Phase I (e.g., oxidation, reduction) or Phase 2 (e.g., conjugation) reactions that occur primarily in the liver. The most common Phase I reaction is oxidation, which involves the insertion of an oxygen atom into the compound to form a polar hydroxyl group. Of the enzymes involved in Phase I reactions, the CYP450 group is the most important.
Cytochromes P-450 are a superfamily of hemoproteins which can be divided into families, subfamilies and/or single enzymes.3 The cytochrome P-450 enzymes act as a major catalyst for drug oxidation. To unify nomenclature, a given gene family is defined as having >40% amino acid sequence homology and a subfamily as having >55% identical sequence homology Using this nomenclature, the cytochrome P450 enzymes are designated by the letters CYP (representing cytochrome P450), followed by an Arabic numeral denoting the family, a letter representing the subfamily (when 2 or more exist) and another Arabic numeral designating the individual gene within the subfamily (e.g., CYP2D6).
Each enzyme is termed an isoform (or isoenzyme) since it is derived from a different gene.5 An important subset of the cytochrome P450 family is the CYP3A4 isoenzyme, which accounts for nearly 60% of the total CYP450 in the liver and approximately 70% in the intestine.6 CYP3A4, which catalyzes the biotransformation of many drugs, is significantly expressed extrahepatically. Extensive metabolism by CYP34A in the gastrointestinal tract contributes to the poor oral bioavailability of many drugs.
Many substrates, inhibitors and inducers of CYP3A4 have been identified. By definition, a substrate is a drug that is metabolized by an enzyme system. An inhibitor decreases the activity of the enzyme and may decrease the metabolism of substrates, generally leading to an increased drug effect. Inducers, however, may increase the metabolism of substrates and generally lead to a decreased drug effect.
Many clinically significant drug interactions have resulted from the inhibition or induction of CYP3A4. High plasma concentrations of terfenadine, for example, occurred when terfenadine (a CYP3A4 substrate) was taken concomitantly with ketoconazole (a CYP3A4 inhibitor), resulting in torsades de pointes, a life-threatening cardiac arrhythmia. The large number of drugs that are either substrates, inducers, or inhibitors of CYP3A4, coupled with the increased awareness of the role of CYP3A4 in drug metabolism has led to increased concern over potentially life-threatening drug interactions.
Drug Interactions Involving the Inhibition of CYP3A4
Terfenadine (Seldane®) and astemizole (Hismanal®) undergo extensive first-pass metabolism in the liver to both inactive and active metabolites by the CYP3A4 isoform. When either drug is co-administered with an inhibitor of CYP3A4, such as an azole antifungal medication or macrolide antibiotic, a build-up of the parent compound takes place, resulting in cardiotoxicity. Specifically, high plasma concentrations of both terfenadine and astemizole have been associated with torsade de pointes, a life-threatening cardiac arrhythmia characterized by altered cardiac repolarization and a prolonged QT interval. In several instances, this drug interaction has been fatal. After several reported deaths in patients taking terfenadine concomitantly with erythromycin or other macrolide antibiotics, the FDA began evaluating whether or not terfenadine should be withdrawn from the market. In February 1998, Hoechst Marion Roussel voluntarily withdrew Seldane® from the market. To counteract any future drug interaction potential, fexofenadine (Allegra®), the active metabolite of terfenadine, has now been marketed as a noncardiotoxic alternative to terfenadine. Fexofenadine is the only nonsedating antihistamine that is not metabolized by the cytochrome P450 enzyme system.
Similar to fexofenadine, loratadine (Claritin®) is not associated with any arrhythmias and is a safe alternative to terfenadine. Inhibition of the metabolism of loratadine, however, has been associated with a significant increase in sedation and central nervous system side effects. Agents which inhibit the metabolism of loratidine include ketoconazole, erythromycin and cimetidine (all inhibitors of CYP3A4).
Cetirizine has not been found to have clinically significant drug interactions with the CYP3A4 inhibitors erythromycin, azithromycin, ketoconazole or low-dose theophylline.8 Higher doses of theophylline (400 mg) have reportedly caused a 16% decrease in the clearance of cetirizine, however. For this reason, fexofenadine is probably safer to use with theophylline.
In the patient currently taking terfenadine or astemizole, the clinician must consider the drug interaction potential of any concurrent medications which may be added to the patient’s medication regimen. When choosing a histamine receptor antagonist, for example, an agent other than cimetidine (a potent CYP3A4 inhibitor) is warranted. Since all of the azole antifungals [ketoconazole (Nizoral®), itraconzole (Sporanox®), and fluconazole (Diflucan®)] are inibitors of CYP3A4, they should be avoided in patients taking these drugs.5 Terbinafine, which is not an inhibitor of CYP3A4, should be used instead. If the patient taking terfenadine or astemizole is in need of an antidepressant, paroxetine, venlafaxine, or one of the tricyclic antidepressants should be considered since none of these drugs inhibit the CYP3A4 isoform to any clinically signficant extent.
Using a nonsedating antihistamine with less potential for interacting with drugs metabolized by the cytrochrome P450 system (such as fexofenadine, or Allegra®) is the safest option for patients taking CYP3A4 inhibitors concomitantly.
Erythromycin and clarithromycin (Biaxin), both potent inhibitors of CYP3A4, can inhibit the metabolism of drugs which are metabolized by CYP3A (e.g., astemizole, cisapride and theophylline). Torsade de pointes and QT-interval prolongation have been reported in patients taking either erythromycin or clarithromycin concurrently with terfenadine.5,8 Erythromycin has also been shown to potentiate the pharmacodynamic effects of warfarin and carbamazepine by inhibiting their metabolism.5,8 Clarithromycin, however, has not been shown to have any effect on the metabolism of warfarin or carbamazepine.
In contrast, azithromycin (Zithromax®) is not an inhibitor of CYP3A4 and is thus considered safe for use with another drug which is metabolized by CYP3A4. In the patient taking terfenadine who needs a macrolide antibiotic, azithromycin should be given to avoid the development of torsade de pointes. Although clarithromycin has not been shown to interact with either warfarin or carbamzepine, azithromycin is probably the safest macrolide for concomitant therapy with these agents.
Theophylline is metabolized by the CYP1A2, CYP2E1, and CYP3A4 isoenzymes.8 Due to its metabolism by CYP1A2, inducing agents such as omeprazole and cigarette smoke increase the clearance of the drug. Thus, larger doses of theophylline may be necessary when patients are taking omeprazole concomitantly or if they currently smoke cigarettes, and the dose decreased when either is discontinued.
Erythromycin and clarithromycin (but not azithromycin) inhibit the metabolism of theophylline, increasing the risk for theophylline toxicity.5 Other CYP3A4 inhibitors that decrease the metabolism of theophylline include ciprofloxacin, enoxacin, clarithromycin, itraconazole, ketoconazole, fluconazole, cimetidine, omeprazole, quinidine, nefazodone, fluoxetine, fluvoxamine, and sertraline.8 Theophylline plasma concentrations can increase to the toxic range if the dose of theophylline is not reduced when given with one of these agents. Indeed, several fatal cases of theophylline toxicity have been reported with the concomitant use of erythromycin and theophylline. Although this interaction is more likely to occur in patients receiving high doses of erythromycin for a long duration of time, fatal interactions have occurred at low doses of erythromycin taken for 5 to 7 days. The risk of theophylline toxicity can be minimized by using concurrent drug(s) that are not metabolized by CYP3A4, or by reducing the theophylline dose while frequently monitoring the patient’s theophylline plasma concentration.
Cisapride, similar to terfenedine, has quinidine – like properties, such that toxic levels of the drug may potentially lead to life-threatening cardiac arrhythmias.8,9 Serious ventricular arrhythmias including ventricular tachycardia, ventricular fibrillation, and torsade de pointes, have been reported in patients taking cisapride (Propulsid®) concomitantly with drugs which are inhibitors of CYP3A4. Torsade de pointes has occurred in patients taking cisapride concomitantly with ketoconazole, fluconazole, itraconazole, metronidazole, erythromycin and clarithromycin. For this reason, cisapride is contraindicated in any patient taking these drugs.
In the patient taking an inhibitor of CYP3A4 who needs a gastrointestinal stimulant, metoclopramide would be a good choice. If for some reason the patient can only take cisapride (e.g.,metoclopramide is contraindicated), drugs which are considered safe for concomitant administration with cisapride include paroxetine, azithromycin, and terbinafine.
HMG-CoA Reductase Inhibitors
The HMG-CoA reductase inhibitors have different pharmacokinetic properties and are metabolized differently. Lovastatin, simvastatin, and atorvastatin are substrates of CYP3A4 (although inhibition of CYP2C9 may also occur to a minor extent).10-13 Fluvastatin is significantly metabolized by CYP2C914 and cerivastatin is metabolized by 2 isoenzymes, CYP3A4 and CYP2C8. In contrast, pravastatin is not significantly metabolized by either CYP3A4 or CYP2C9. These differences in drug metabolism among the statins may account for their different drug-interaction profiles. Statins that are substrates of CYP3A4 have the greatest potential for interacting with drugs known to inhibit the CYP450 system, increasing the concentrations of substrate and the potential for adverse drug interactions.
Drug interactions between the HMG-CoA reductase inhibitors that are substrates of CYP3A4 (e.g., lovastatin, simvastatin, atorvastatin and cerivastatin) and drugs that inhibit CYP3A4 may result in increased concentration of the statin and possibly myopathy and varying degrees of rhabdomyolysis (injury to the plasma membrane of skeletal muscle, resulting in leakage of its components into the blood or urine). Rhabdomyolysis is a serious condition which can be fatal if not detected prior to the onset of acute renal failure in any patient taking a statin.
Lovastatin Drug Interactions
All inhibitors of CYP3A4, such as itraconazole, erythromycin, and grapefruit juice, are susceptible to interactions with lovastatin. In a double-blind, randomized, two-phase, crossover study, 12 subjects were given either itraconazole 200 mg or placebo orally once daily for four days, followed by a single 40 mg dose of lovastatin on day four. The concomitant administration of itraconazole with lovastatin was found to significantly increase the plasma concentrations of both lovastatin and lovastatin acid, the active metabolite. In one subject, the plasma CK level, a sign of muscle damage, was elevated 10-fold within 24 hours of the administration of lovastatin during the itraconazole phase, but not during the placebo phase.
As the results of this study demonstrate, inhibition of CYP3A4-mediated metabolism probably explains the increased toxicity of lovastatin observed with the coadministration of itraconazole. This is further illustrated in a case report in which a patient experienced rhabdomyolysis when lovastatin was given concomitantly with itraconazole. Other inhibitors of CYP3A4 also have the potential to compete for the active site of the enzyme. Rhabdomyolysis has been reported in patients with and without renal insufficiency who were treated with lovastatin plus erythromycin. Rhabdomyolysis and nonoliguric acute renal failure have also been reported in two heart transplant patients treated with lovastatin and cyclosporine.
Since the first report of a grapefruit juice-drug interaction by Bailey et al, grapefruit juice has been shown to increase the bioavailability of many other drugs metabolized by CYP3A4. The serum levels of lovastatin and lovastatin acid are signficantly increased when taken with grapefruit juice.
Simvastatin Drug Interactions
The coadministration of itraconazole with simvastatin has been associated with rhabdomyolysis. Itraconazole has been shown to significantly increase the serum concentration of simvastatin and its active metabolite, simvastatin acid, in a double-blind, two-phase crossover study. Two case reports of simvastatin-induced rhabdomyolysis in patients who received itraconazole also exist in the literature. In one case, a patient with normal renal function who had been stable on a simvastatin regimen for several months developed rhabdomyolysis after taking itraconazole for a fungal infection. In another case, a renal transplant patient receiving cyclosporine and simvastatin developed myopathy and a markedly elevated CK level after starting itraconazole therapy.
Cyclosporine has also been found to interact with simvastatin, most likely by competitive inhibition of CYP3A4. Plasma concentrations of simvastatin beta-hydroxy acid, the active metabolite of simvastatin, were found to be higher in heart transplant recipients receiving cyclosporine than in patients who had not had heart transplants (both of which were receiving long-term simvastatin therapy). The concomitant administration of cyclosporine with simvastatin in the heart transplant patients appeared to cause a reduced metabolic clearance of simvastatin and the buildup of the active metabolite. In a recent study in heart transplant recipients, the incidence of rhabdomyolysis was low (3.6%) in patients treated with simvastatin, while no cases were reported in the pravastatin treatment group. All patients in this study were receiving concomitant cyclosporine, azathioprine, and prednisone.
In another study, 5 kidney transplant recipients treated with cyclosporine, azathioprine, and prednisolone were given single 20 mg doses of simvastatin and compared with 5 patients treated with azathioprine and prednisolone (without cyclosporine).38 The mean area under the curve (AUC) of simvastatin was found to be approximately 3 times higher in the patients receiving cyclosporine compared with the patients not receiving cyclosporine, and the mean peak plasma concentration was twice as high in patients receiving cyclosporine as in those not receiving cyclosporine. In a case report, a renal transplant patient receiving cyclosporine and simvastatin developed rhabdomyolysis after taking clarithromycin for a soft-tissue infection. The interaction of clarithromycin with cyclosporine resulted in markedly increased cyclosporine concentrations and an increased risk for myopathy due to simvastatin. In addition, clarithromycin may have also directly increased simvastatin concentrations.
Simvastatin-induced myopathy has also been reported in a patient taking simvastatin concomitantly with diltiazem, who developed a CK level 100 times the ULN (normal range = 50 – 170 units/ Liter). This case of myopathy was likely due to a drug interaction between simvastatin and diltiazem. Myositis and rhabdomyolysis also developed in a patient who had been taking simvastatin for 19 weeks when the patient was started on nefazodone. Nefazodone, an inhibitor of CYP3A4, inhibited the metabolizm of simvastatin sufficiently to cause an increase in simvastatin plasma concentrations and rhabdomyolysis.
Rhabdomyolysis has also been reported in a patient taking simvastatin concomitantly with the calcium channel antagonist mibefradil. A total of 19 cases of simvastatin-induced rhabdomyolysis were reported to Hoffman-La Roche. Nine of these patients were also receiving concomitant cyclosporine. Seven reports to the US Food and Drug Administration (FDA) of simvastatin-associated muscle injury in patients taking mibefradil with simvastatin led the FDA to issue a Talk Paper warning of possible rhabdomyolysis with mibefradil and certain statins, and eventually to the withdrawal of mibefradil from the market in June 1998. Based on these reports, simvastatin should be administered with extreme caution to patients receiving CYP3A4 inhibitors.
Atorvastatin Drug Interactions
Atorvastatin is also metabolized by CYP3A4. In a pharmacokinetic study, the concomitant administration of erythromycin with atorvastatin was found to produce a moderate increase in atorvastatin plasma concentrations. The mean AUC of atorvastatin was increased by 33% when it was administered with erythromycin. The mean half-life of atorvastatin remained unchanged. The active metabolites of atorvastatin have a long half-life (up to 57 hours), and their serum concentrations potentially could increase with multiple dosing. However using specific bioanalytical methodology, much larger changes in the AUC and half-life of atorvastatin (about threefold) were observed in an interaction study with itraconazole. Since atorvastatin is metabolized by CYP3A4, atorvastatin should be used with caution with known CYP3A4 inhibitors (e.g., itraconazole, diltiazem, etc.) until further research is conducted.
Cerivastatin Drug Interactions
Cerivastatin is metabolized by CYP3A45 and CYP2C8. In a phase I study involving 8 patients, cimetidine had no clinically significant effects on the pharmacokinetics of cerivastatin. The concomitant administration of cimetidine and cerivastatin appeared to be well tolerated, and no adverse events were observed. Although cimetidine appears not to interact with cerivastatin, cerivastatin may interact with other substrates or inhibitors of CYP3A4. Until relevant data are available, cerivastatin should be used prudently with other CYP3A4 inhibitors.
Fluvastatin Drug Interactions
Unlike other statins, which are CYP3A4 substrates, fluvastatin is significantly metabolized by CYP2C9.24 In a pharmacokinetic study using diclofenac oxidation as a marker of CYP2C9 activity, fluvastatin was found to be a potent inhibitor of CYP2C9 (as demonstrated by an increase in diclofenac AUC and a decrease in diclofenac oral clearance). These results suggest that the concomitant administration of fluvastatin with drugs that are CYP2C9 substrates (such as phenytoin, oral anticoagulants, certain oral hypoglycemic agents, and certain nonsteroidal anti-inflammatory agents) may lead to an increase in serum concentrations of these drugs.
The concomitant administration of fluvastatin with S-warfarin, for example, may inhibit S-warfarin metabolism and produce marked increases in prothrombin time measurements and bleeding. Currently, 6 case reports of increased prothrombin times and international normalized ratios (INR) resulting from the concomitant administration of warfarin and fluvastatin exist in the literature. Although none of the patients experienced any clinically significant bleeding, all required a reduction in warfarin dosage in order to be within their therapeutic range. Since warfarin is metabolized by CYP2C9, it is likely that fluvastatin inhibited the metabolism of warfarin in all of these cases.
The simultaneous administration of fluvastatin with phenytoin may also inhibit the metabolism of phenytoin, such that the patient may experience symptoms of phenytoin toxicity. The concomitant administration of fluvastatin with certain oral hypoglycemics may result in poor diabetic control and low blood glucose concentrations. Similarly, the coadministration of fluvastatin with certain non-steroidal anti-inflammatory agents may increase the frequency and severity of adverse drug reactions associated with this class of drugs, such as gastritis and nephrotoxicity.
Although there are no case reports in the literature to date with regard to these specific drug interactions, the pharmacist should be aware of the potential for these interactions to occur. This is especially important if a patient taking fluvastatin concomitantly with any of these drugs complains of increased frequency or severity of adverse drug reactions.
Pravastatin Drug Interactions
Pravastatin is not extensively metabolized by CYP3A4, CYP2C8, or CYP2C9. Pravastatin differs from the other statins in that it is highly specific for the liver. Pravastatin, which is hydrophylic, primarily inhibits cholesterol synthesis in liver cells, or hepatocytes. Since hydrophylic compounds are unable to penetrate cell membranes by diffusion or pores, a carrier-mediated transport mechanism has been postulated as the means by which pravastatin is taken up by hepatocytes.
Transport systems for the liver include a Na+/K+ATPase, a sodium-dependent cotransporter for bile acids (cholate and taurocholate), a sodium-independent transport system for bile acids, and carriers for organic cations (e.g., vecuronium), organic anions (e.g., bilirubin, rifampicin), amino acids, and long-chain fatty acids (which are sodium-dependent or not). There is also a carrier for the facilitated diffusion of glucose. Of these carrier-mediated transport systems, pravastatin has been shown to have a high affinity for the sodium-independent uptake system for bile acids. Hence the tissue selectivity of pravastatin is due to its high affinity for this bile acid transporter, which exits primarily in the hepatocyte membrane.
Ten cardiac transplant patients treated with cyclosporine, prednisone, and azathioprine were given single 20 mg doses of pravastatin. The mean peak plasma concentration of pravastatin was 7-fold higher and the mean AUC was 20-fold higher in patients receiving concomitant cyclosporine compared with nontransplant historical controls. However, this study was complicated by poor study design (i.e., the cardiac transplant cohort was in poor health and required additional medications). In renal transplant patients, mean AUC values of pravastatin were 5 to 7 fold higher in patients receiving concomitant cyclosporine than those reported for historical controls, compared with a 20-fold increase in lovastatin mean AUC values experienced by patients receiving lovastatin plus cyclosporine. Pravastatin did not accumulate with multiple doses, while patients receiving lovastatin experienced a 40% to 50% increase in AUC after multiple dosing. There are no reports in the literature of rhabdomyolysis occurring in patients receiving concomitant pravastatin and cyclosporine therapy.
In healthy volunteers, itraconazole slightly increased the AUC and peak plasma concentration of pravastatin, but these changes were not statistically significant. Diltiazem 120 mg has also been shown to have no significant effects on the pharmacokinetics of pravastatin. Since drug interaction studies with pravastatin are limited, additional studies and clinical experience are necessary to fully evaluate the drug-interaction potential of pravastatin. Given the fact that pravastatin is not metabolized to a clinically significant extent by CYP3A4, CYP2C8, or CYP2C9 (but rather is selectively taken up by the sodium-independent bile acid transporter), one would expect that the potential for drug interactions with other CYP3A4 substrates, inhibitors, or inducers to be reduced. Until such data is available, however, it is prudent for the clinician to be aware of the potential for pravastatin to interact with drugs metabolized by the cytochrome P450 system.
Drug Interactions With Inducers of CYP3A
Due to the resurgence of tuberculosis in the United States, rifampin (Rifadin®, Rimactane®), an inducer of CYP3A4, is being utilized more frequently. Of clinical significance is the reduction of efficacy of oral contraceptives when taken concomitantly with rifampin. This results from decreased plasma concentrations of estradiol (a substrate of CYP3A4), which can be reduced by induction of CYP3A4 enzymes mediated by rifampin. Other inducers of CYP3A4 include phenytoin, phenobarbital, troglitazone, and carbamazepine. Potent glucocorticoids such as dexamethasone (Decadron®) are also inducers of CYP3A4, whereas lower potency glucocorticoids (e.g., prednisolone) have a minimal effect on the induction of CYP3A4.
Drug Interactions Involving the Inhibition of CYP1A2
The quinolone antibiotics have the potential to inhibit the metabolism of theophylline (a substrate of CYP1A2) through CYP1A2 inhibition. The degree of CYP1A2 inhibition varies with the quinolone (inhibitory potency of the fluoroquinolones: enoxacin > ciprofloxacin > norfloxacin >> ofloxacin). When enoxacin (Penetrex®) and ciprofloxacin (Cipro®) are taken concomitantly with theophylline, they have the highest potential to elevate theophylline plasma concentrations when theophylline levels are at the upper end of the therapeutic range. In contrast, norfloxacin (Noroxin) and ofloxacin (Floxin®) have minimal effects on theophylline metabolism and plasma concentrations. Lomefloxacin (Maxaquin®) also does not appear to alter the metabolism of theophylline.
Cimetidine is also an inhbitor of CYP1A2. The inhibiton of CYP1A2 by cimetidine is dose-related. Clinically significant drug interactions usually occur when the daily dose of cimetidine approaches 1 gm or when multiple inhibitors of the enzyme are present. The most clinically significant drug interactions with cimetidine are with CYP1A2 substrates having a narrow-therapeutic-index, such as theophylline, procainamide, and R-warfarin. Concomitant administration of cimetidine with any of these drugs has the potential to result in drug toxicity.
Drug Interactions With Inducers of CYP1A2
Charbroiled foods and cigarette smoke, which contain polycyclic aromatic hydrocarbons, are inducers of CYP1A2. This is the only isoform affected by cigarette smoke. Cigarette smoking can elevate the activity of CYP1A2 by as much as 3-fold, which explains why smokers require much higher doses of theophylline (a substrate of CYP1A2) than non-smokers.
Many antidepressants are metabolized by CYP2D6. In addition to being substrates of CYP2D6, the selective serotonin reuptake inhibitors (SSRIs) are also inhibitors of CYP2D6. Among inhibitors of this isoform, paroxetine (Paxil®) exhibits the greatest potential to inhibit the metabolism of CYP2D6 substrates. This is followed by fluoxetine (Prozac®), sertraline (Zoloft®), fluvoxamine (Luvox®), nefazodone (Serzone®) and venlafaxine (Effexor®), clomipramine (Anafranil®) and amitriptyline (Elavil®).
In making a therapeutic recommendation, the clinician must consider both the efficacy and safety of a drug. Many drugs are substrates or inhibitors of CYP3A4, and thus have the potential to interact with other drugs which are metabolized by CYP3A4, such as erythromycin and itraconazole. The resulting increased serum concentration of the drug can produce serious adverse events, and in some cases, may even be fatal. Patients with multiple risk factors for cardiovascular disease and elderly patients receiving polypharmacy are particulary susceptible to drug interactions. By understanding the role of the cytochrome P450 enzyme system in drug metabolism, clinicians should be able to predict and avoid clinically significant drug interactions.