With the increasing development of newer and more complex drug compounds, pharmacists are being asked to bear much of the burden for detecting, preventing, and resolving adverse drug reactions and potentially serious drug interactions. Factors that contribute to drug interactions can be easily identified, but knowing how to prevent interactions is far more difficult. Drug interactions can mislead clinicians into misinterpreting these effects as unrelated to adverse drugñdrug interactions. The following scenario illustrates the quandary in which pharmacists find themselves in evaluating drug interactions to determine safe use: A physician contacts a pharmacist and asks which selective serotonin reuptake inhibitor (SSRI) can be used safely in a patient taking multiple medications (i.e., warfarin, thiazide diuretic, beta blocker, and codeine). Since there is a high potential for clinically significant drug interactions with these drugs, advising this clinician will require some thought and research.
National concern about drug interactions with cytochrome P (CYP)-450 enzymes was heightened when fatal cardiac arrhythmias were suspected to be connected to enzymatic interactions between terfenadine and erythromycin or ketoconazole.1,2 As a result, terfenadine was withdrawn from the market. Later, mibefradil and cisapride were withdrawn due to their high potential for inhibiting certain CYP enzymes and causing fatal cardiac arrhythmias when combined with certain CYP-enzyme inhibitors. As a consequence, some drugs marketed in the last two decades--especially antidepressants--that have been associated with serious drugñdrug interactions have been subject to careful scientific examination.
Because chronic illnesses, especially depression, require extended periods of treatment, the probability of co-administration of additional medications is high. The increased prevalence of depression in both the young and the elderly populations has led to the addition of antidepressants to complex medication regimens. In 2006, antidepressant utilization in the United States was extensive. Three of the top 15 and five of the top 50 brand drugs dispensed by pharmacies were antidepressants, as were 10 of the top 200 generic drugs.3
Drug interactions are of concern because the outcome of concurrent drug administration is diminished therapeutic efficacy or increased toxicity of one or more of the administered compounds. Mechanisms of drug interactions are usually divided into two major categories, pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions consist of changes in the absorption, distribution, metabolism, or excretion of a drug or its metabolites, or the quantity of active drug that reaches its site of action, after the addition of another chemical agent. Metabolically-based drug interactions are the most frequent interaction encountered in clinical practice. Pharmacodynamic interactions occur when two drugs act at the same or interrelated receptor sites, resulting in additive, synergistic, or antagonistic effects. The purpose of this article is to give pharmacists an overview of metabolic drugñdrug interactions involving SSRIs.
Drug Metabolism and Overview of the CYP System
Psychotropic drugs, including many antidepressants, are usually lipophilic and are extensively metabolized in the liver through phase I oxidative reactions followed by phase II glucuronide conjugation. Most pharmacokinetic interactions with psychotropic drugs occur at the metabolic level and primarily involve the CYP mono-oxygenases. In some instances, the metabolite of the parent compound has a greater inhibitory effect on the metabolizing CYP isoenzyme(s). Thus, the potential for drug interactions may be greater in clinical practice, where patients may receive higher initial doses or receive doses that are titrated to reach steady-state levels.4
Enzymes of the CYP system are classified into families, subfamilies, and isoenzymes based on similarities in the sequences of their amino acids.5,6 CYP enzymes are responsible for the oxidative metabolism of xenobiotics (drugs and other exogenous chemicals), as well as many endogenous compounds such as prostaglandins, fatty acids, and steroids. The first Arabic number designates the enzyme family, the capital letter indicates the subfamily, and the second number designates individual isoenzymes. The major CYP enzymes involved in drug metabolism in humans belong to families 1, 2, and 3, the specific isoforms being CYP-1A2, CYP-2C9, CYP-2C19, CYP-2D6, and CYP-3A4. (Due to their identical structure and enzymatic action, CYP-3A3 and CYP-4 are often combined and referred to as CYP-3A4.) Each CYP isoform is a specific gene product and possesses a characteristic broad spectrum of substrate specificity. The activity of these isoenzymes is genetically determined and is greatly influenced by environmental factors, such as concomitant administration of other drugs.
Drug interactions involving CYP isoforms generally result from one of two processes: enzyme inhibition and enzyme induction. Enzyme inhibition usually involves competition with another drug for the enzyme-binding site. Drug-induced inhibition of CYP enzymes is usually due to competitive binding at enzyme-binding sites, and it generally occurs within a few hours.7-9 The magnitude of the inhibition is a function of the plasma concentration of the inhibiting agent. Thus, the half-life of the inhibitor drug will determine how long it must be administered before the full inhibitory effect on CYP enzymes is achieved and, conversely, how long after its discontinuation the inhibition phase will endure.
Enzyme induction occurs when a drug stimulates the synthesis of more enzyme protein, enhancing the enzyme's metabolizing capacity. Induction of the gene responsible for the production of the enzyme increases its rate of synthesis of the drug, thus increasing the cellular content and activity of the induced CYP enzymes.10-12 Since enzyme induction generally involves protein synthesis, there is a time delay in both the onset and the offset relative to starting and stopping the inducing agent. Therefore, the full effect of the inducer 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 inducer agent has been discontinued and the rate of enzyme production has returned to baseline.
Currently, five types of SSRIs are marketed in the United States: fluoxetine, fluvoxamine, paroxetine, sertraline, and citalopram. These drugs are subject to extensive oxidative metabolism in the liver. Because these antidepressants have a wide therapeutic index, inhibition or induction of their metabolism is unlikely to be of great concern. However, SSRIs may cause a clinically relevant inhibition of CYP enzymes, and care must be exercised when an SSRI is being added to a multidrug regimen. As shown in TABLE 1, SSRIs differ considerably in their ability to inhibit individual CYP enzymes. This may help guide selection of an appropriate compound for the individual patient.12,13 The inhibitory effect on CYP enzymes is concentration-dependent; the potential for drug interactions with citalopram and paroxetine is higher in the elderly because the elimination of these drugs may be affected by age. This is especially true with drugs such as fluoxetine, which exhibits nonlinear kinetics.
Fluoxetine is marketed as a racemic mixture of two enantiomers.14 The major metabolic pathway of fluoxetine is N-demethylation to form the active metabolite norfluoxetine. In vivo studies have indicated that CYP-2D6 is the major isoform responsible for the N-demethylation of fluoxetine. In vitro evidence, however, suggests that other isoenzymes, including CYP-2C9, CYP-2C19, and CYP-3A4, also may contribute to this reaction. Fluoxetine and its metabolite norfluoxetine have important inhibitory effects on CYP enzymes in vitro. They were found to inhibit CYP-2D6 markedly, CYP-2C9 moderately, and CYP-2C19 and CYP-3A4 mildly to moderately.
Fluoxetine follows nonlinear kinetics, and its plasma concentrations increase to a greater extent than the increase in drug dosages would predict. When fluoxetine is taken routinely, it takes about one month for it to reach a steady-state level in the blood and cause a drug interaction. Due to the long elimination half-lives of fluoxetine (one to four days) and norfluoxetine (seven to five days), inhibition of CYP enzymes may persist for up to six weeks after discontinuation of the antidepressant, a situation that complicates patient management.
Drug Interactions: Fluoxetine 20-60 mg/day may cause a two- to fourfold increase in plasma concentrations of desipramine, possibly associated with signs of toxicity including decreased energy, psychomotor retardation, sedation, dry mouth, and memory loss.15,16 The mechanism of this interaction may be attributed to the potent inhibitory effect of fluoxetine and norfluoxetine on the CYP-2D6ñmediated hydroxylation of tricyclic antidepressants (TCAs). When given in combination with the heterocyclic antidepressant trazodone, fluoxetine was found to produce a significant elevation in plasma levels of both trazodone and its metabolite metachlorophenylpiperazine (mCPP).15,17 This reaction is probably caused by the inhibition of CYP-2D6 and CYP-3A4 in the metabolism of trazodone and by CYP-2D6 inhibition of mCPP metabolism.
Fluoxetine has been reported to produce a remarkable increase in plasma concentrations of traditional antipsychotics such as haloperidol and fluphenazine, metabolized at least in part by CYP-2D6, possibly leading to adverse central nervous system (CNS) effects such as extrapyramidal symptoms and impaired psychomotor performance. 15,18 Fluoxetine also may interfere with the elimination of some new atypical antipsychotics. With the coadministration of clozapine and fluoxetine 20 mg/day, one report showed an increase of 50% to 100% in plasma concentrations of cloza!= pine, an atypical antipsychotic metabolized by CYP-1A2 and, to a lesser extent, by CYP-3A4, CYP-2D6, and CYP-2C19.15,19 Concomitant treatment with fluoxetine 20 mg/day in psychotic patients stabilized on risperidone, an antipsychotic whose metabolism is largely dependent on CYP-2D6 and CYP-3A4, was associated with a mean fourfold increase in plasma concentrations of risperidone.20 As a consequence, the active fraction of risperidone (sum of plasma concentrations of risperidone and its active metabolite) increased by 76% over pretreatment. Patients reported the occurrence of akathisia and parkinsonian symptoms requiring anticholinergic medication.21
Fluoxetine may impair the elimination of some benzodiazepines such as diazepam and alprazolam through inhibition of the major CYP isoforms mediating their metabolism, in particular CYP-2C19 (diazepam) and CYP-3A4 (diazepam, alprazolam).15,21,22 As benzodiazepines have a wide therapeutic index, however, the clinical significance of these interactions is probably limited. Fluoxetine also may impair the elimination of phenytoin, as documented by many case reports of toxic phenytoin concentrations occurring shortly after the addition of fluoxetine.15,23 This interaction is probably explained by the moderate inhibitory effect of fluoxetine on the CYP-2C9ñmediated metabolism of phenytoin.24
A clinically significant interaction can occur between fluoxetine and warfarin, resulting in enhanced anticoagulant activity and a subsequent risk of hemorrhagic complications, as well as marked elevation of the international normalized ratio (INR) and prolongation of prothrombin time, in patients stabilized on warfarin.15,25 The inhibitory effect of fluoxetine on CYP-2C9ñmediated metabolism of active S-warfarin is the most likely explanation for this potentially serious drug interaction. Since warfarin is a racemic mixture with an active S -enantiomer and a less active R-enantiomer, S-warfarin is metabolized by CYP-2C9, while R-warfarin is metabolized by CYP-1A2 and, to a lesser extent, CYP-2C19 and CYP-3A4. In addition to being metabolized by these isoenzymes, R-warfarin inhibits CYP-2C9 activity, thus increasing the effect of active S-warfarin.26
There are some reports of potentially dangerous interactions between fluoxetine and certain cardiovascular agents. Inhibition of the oxidative metabolism of beta blockers (metoprolol, propranolol), which is partly mediated by CYP-2D6, may explain the occurrence of severe bradycardia or heart block in patients after coadministration of fluoxetine.15,27 The combination of fluoxetine and the calcium channel blockers nifedipine and verapamil has been reported to be associated with signs of toxicity such as edema, nausea, and flushing that disappeared when the dose of the calcium channel antagonists was reduced. 15,28 Inhibition of CYP-3A4ñmediated metabolism of verapamil and nifedi!= pine by fluoxetine and its metabolite norfluoxetine may explain the occurrence of this interaction.
The major metabolic pathways of fluvoxamine are oxidative demethylation and oxidative deamination by CYP-2D6 and CYP-1A2.15,29 Fluvoxamine interacts with several CYP isoenzymes. It is a potent inhibitor of CYP-1A2 and CYP-2C19 and a moderate inhibitor of CYP-2C9 and CYP-3A4; it affects CYP-2D6 activity only slightly. 30 As a result of this nonselective inhibition of various CYP isoenzymes, fluvoxamine has a high potential for metabolic drug interactions.
Drug Interactions: Fluvoxamine may increase the plasma concentrations of certain antidepressants. Fluvoxamine affects predominantly the demethylation pathways of TCAs through inhibition of CYP-2C19 and, to a lesser extent, CYP-1A2 and CYP-3A4. Accordingly, plasma levels of the tertiary amines amitriptyline, imipramine, and clomipramine have been reported to increase by up to fourfold during coadministration with fluvoxamine 100 mg/day, possibly leading to toxic effects, while concentrations of the secondary amine desipramine were only slightly modified.31 A recent report documented that the addition of fluvoxamine 50-100 mg/day caused a three- to fourfold increase in plasma concentrations of mirtazapine, a new antidepressant metabolized mainly by CYP-1A2, CYP-2D6, and CYP-3A4.32
Fluvoxamine may interfere with the biotransformation of various antipsychotics. The addition of fluvoxamine 50-300 mg/day to haloperidol maintenance therapy in patients with schizophrenia resulted in a 1.8- to 4.2-fold increase in serum haloperidol concentrations.33 This interaction is likely explained by the inhibitory effect of fluvoxamine on CYP-1A2 and CYP-3A4, which are involved in the metabolism of haloperidol.
Clinically relevant metabolic interactions may occur between fluvoxamine and the atypical antipsychotics clozapine and olanzapine. Researchers have clearly documented that fluvoxamine may increase plasma clozapine concentration up to five- to 10-fold, possibly resulting in toxic effects.34 Therefore, the combination of fluvoxamine and clozapine must be carefully monitored, and the use of low doses of both compounds is advisable. This interaction is attributed not only to inhibition of CYP-1A2, the major enzyme responsible for clozapine metabolism, but also to additional inhibitory effects of fluvoxamine on CYP-2C19 and CYP-3A4.
Fluvoxamine may elevate plasma levels of olanza!= pine by approximately twofold.35 The potent inhibitory effect of fluvoxamine on CYP-1A2, one of the major isoforms responsible for olanzapine biotransformation, provides a rational explanation for this interaction. Fluvoxamine also has been reported to decrease the metabolic clearance of some benzodiazepines, including alprazolam, which is metabolized primarily by CYP-3A4, and diazepam, which is substrate for both CYP-2C19 and CYP-3A4.36,37
Potentially dangerous consequences resulting from the combined use of fluvoxamine and theophylline have been documented.38 Concomitant treatment with fluvoxamine may cause a marked elevation in plasma theophylline levels associated with signs of theophylline toxicity, including ventricular tachycardia, anorexia, nausea, and seizures. This interaction is presumably mediated by the inhibitory effect of fluvoxamine on the activity of CYP-1A2, which is the main isoenzyme involved in theophylline metabolism. Theophylline toxicity is a serious, sometimes fatal, medical condition, so fluvoxamine should be avoided in patients taking theophylline.
A potentially dangerous interaction may occur between fluvoxamine and warfarin. The addition of fluvoxa!= mine for two weeks to a stable regimen of warfarin produced a 65% increase in plasma warfarin concentration and a significant prolongation of prothrombin time.15 In one report, the addition of a low dose of fluvoxamine in the case of an elderly woman with atrial fibrillation that was stabilized on warfarin resulted in a marked elevation of her INR that persisted for two weeks after the antidepressant was stopped.39 The mechanism of this interaction is particularly complex. In fact, fluvoxamine may directly increase plasma levels of S-warfarin through its moderate inhibitory effect on CYP-2C9. In addition, fluvoxamine, a strong inhibitor of CYP-1A2, is expected to elevate R-warfarin levels, which in turn would reduce CYP-2C9 activity and thus increase the effect of the active S -warfarin.25
In a study of healthy volunteers, coadministration of fluvoxamine 100 mg/day with propranolol 160 mg/day resulted in a fivefold increase in plasma propranolol concentrations that was associated with a slight potentiation of the propranolol-induced reductions in heart rate and exercise diastolic blood pressure.15 This effect is likely to be the consequence of an inhibitory effect of fluvoxamine on CYP-1A2 and CYP-2C19, the major isoforms involved in the biotransformation of this beta blocker.
In addicted patients on maintenance treatment with methadone--a synthetic opioid predominantly metabolized via CYP-3A4--fluvoxamine, but not fluoxetine, was found to increase plasma concentrations of both methadone enantiomers by 30% to 50%. 40,41 As is the case with fluoxetine, fluvoxamine may cause potentially serious interactions if it is coadministered with CYP-3A4 substrates.
Among the SSRIs, paroxetine is the most potent in vitro inhibitor of CYP-2D6, although it affects other CYP isoforms only minimally.15,42 Paroxetine therefore has the potential to cause clinically significant drug interactions when coadministered with CYP-2D6 substrates. It undergoes extensive hepatic biotransformation, including oxidative cleavage mediated by CYP enzymes, while methylation reactions are probably mediated by catechol-O -methyltransferase. Oxidation of paroxetine is likely catalyzed by a main pathway mediated by CYP-2D6, whose saturation is responsible for the drug's nonlinear kinetics (i.e., plasma concentrations increase to a greater extent than the increase in drug dosages would predict), and by a secondary pathway presumably mediated by CYP-3A4. This isoenzyme is usually responsible for 25% of biotransformation, but becomes more significant at higher plasma concentrations.43 An intermediate metabolite of paroxetine has been shown to have inhibitory activity against CYP-2D6.
Drug Interactions: Like fluoxetine, paroxetine may inhibit CYP-2D6ñmediated hydroxylation of TCAs, possibly leading to adverse effects. When paroxetine was dosed at 20 mg/day and under steady-state conditions, it increased plasma concentrations of desipramine (a substrate of CYP-2D6) from 327% to 421%.44,45 Paroxetine may impair the elimination of older and newer antipsychotics metabolized by CYP-2D6. In a study of healthy volunteers, paroxetine was found to cause a two- to 13-fold increase in single-dose perphenazine peak plasma concentrations, with associated CNS effects such as sedation and extrapyramidal symptoms.46
Paroxetine 20 mg/day given to patients with schizophrenia produced a three- to ninefold elevation in plasma levels of risperidone, resulting in a mean 45% increase in plasma concentrations of the active fraction of risperidone.15 These changes were associated with the occurrence or worsening of extrapyramidal side effects. Other studies have reported that paroxetine may produce a moderate elevation in plasma concentrations of clozapine.47
The major metabolic pathway of sertraline is N-demethylation to form N -desmethylsertraline, which is less potent than the parent drug as a serotonin reuptake blocker. CYP-3A4 is the major isoform responsible for this reaction, but other isoenzymes, including CYP-2D6, probably are involved.48 In vitro studies have documented that sertraline is a mild to moderate inhibitor of CYP-2D6 and a weak inhibitor of the other CYP isoenzymes; this accounts for its favorable interaction profile.15,44
Drug Interactions: Sertraline 50 mg/day was found to cause modifications in plasma concentrations of TCAs, but these were less pronounced compared with other SSRIs.49 Because the inhibition of CYP-2D6 is dose-dependent, however, significant increases in plasma concentrations of TCAs may occur when higher dosages of sertraline are administered.50
Citalopram is a racemic mixture, with its antidepressant effects attributed exclusively to the S (+)-enantiomer. S-citalopram (escitalopram) was recently introduced as an antidepressant.15 The major CYP isoenzymes involved in the metabolism of citalopram are CYP-2C19 and CYP-2D6, with didesmethylcitalopram being the final metabolite. In vitro studies have indicated that CYP-3A4 also is involved in the N-demethylation of citalopram. Citalopram is a weak in vitro inhibitor of CYP-2D6, and it has weak or no effects on CYP-1A2, CYP-2C19, and CYP-3A4.51
Drug Interactions: With respect to pharmacokinetic drug interactions, citalopram is not the cause or the source of clinically significant drug interactions. Therefore, it is considered the safest SSRI to use in clinical practice.
Venlafaxine, a serotonin and noradrenaline reuptake inhibitor, is biotransformed to a major active metabolite, O-desmethylvenlafaxine, and is in parallel with N -desmethylvenlafaxine. In vitro and in vivo studies reported that the O -demethylation of venlafaxine is catalyzed mainly by CYP-2D6, while CYP-3A4 is probably involved in the N-demethylation pathway.15,52 In vitro studies demonstrated that venlafaxine is a weak inhibitor of CYP-2D6, but is considerably less potent than paroxetine, fluoxetine, fluvoxamine, and sertraline and does not significantly affect the activity of CYP-1A2, CYP-2C9, and CYP-3A4. Venlafaxine has a relatively short half-life of five to 11 hours, takes three to five days to reach steady state, and may be associated with clinical drug interactions soon after treatment is initiated.
Drug Interactions: Based on in vitro evidence, venlafaxine appears to have minimal effects on the pharmacokinetics of other drugs.16,53 When venlafaxine was dosed at 150 mg/day in healthy subjects, imipramine and desipramine clearance was slightly reduced, leading to significant increases in their area under the curve (AUC) of 27% and 40%, respectively. In another in vivo study, coadministration of venlafaxine 150 mg/day, with a single 1-mg dose of risperidone, slightly inhibited its conversion of risperidone to 9-hydroxyrisperidone (9-OH-risperidone), which is partially metabolized by CYP-2D6. Although the exact mechanism remains uncertain, venlafaxine caused a 70% increase in the AUC of coadministered haloperidol.
Mirtazapine is the first in a new class of antidepressants, the noradrenergic and specific serotonergic antidepressants. Its effect appears to be related to its dual enhancement of central noradrenergic and serotonin 5-HT1 receptorñmediated serotonergic neurotransmission. Mirtazapine is extensively metabolized in the liver; its major metabolic routes are N -demethylation, N-oxidation, and 8-hydroxylation. CYP-2D6 and, to a lesser extent, CYP-3A4 are involved in the formation of hydroxymetabolites. CYP-3A4 and CYP-1A2 catalyze the N-demethylation, while CYP-3A4 is the major isoform involved in N-oxidation.15,54
Drug Interactions: Mirtazapine has minimal inhibitory effects on CYP-1A2, CYP-2D6, and CYP-3A4. Therefore, it is not expected to cause clinically significant interactions with substrates of these isoforms.
Nefazodone is a potent serotonin 5-HT
2 receptor antagonist that inhibits both serotonin and noradrenaline
reuptake. It is extensively metabolized in the liver by hydroxylation and
dealkylation, primarily via CYP-3A4.15,55 Hydroxynefazodone, the
major metabolite, displays pharmacologic activity similar to its parent drug.
Other minor metabolites include mCPP and a triazoledione derivative, both of
which are less active than nefazodone. Nefazodone has been shown in vitro to
be a potent inhibitor of CYP-3A4; it also has a weak inhibitory effect on
CYP-2D6 activity, presumably due to mCPP.
Drug Interactions: When nefazodone 200 mg twice daily was given to healthy volunteers for seven days, results included an increase in plasma concentrations of triazolam and alprazolam--substrates of CYP-3A4--of 98% and 290%, respectively.15,56
The most clinically important drug interactions with nefazodone may occur when this agent is given in combination with CYP-3A4 substrates with a narrow therapeutic index. One study documented the occurrence of nephrotoxicity and neurotoxicity when nefazodone was associated with the immunosuppressants cyclosporin and tacrolimus, and of myositis and rhabdomyolysis with simvastatin.15,56 Concomitant use of nefazodone and certain CYP-3A4 substrates, including cisapride, astemizole, terfenadine, and loratadine, is contraindicated, as it may predispose patients to torsades de pointes, a potentially fatal ventricular dysrhythmia associated with marked electrocardiographic QTc prolongation.57
The Pharmacist's Role
There is no comprehensive guide, chart, or computer software program to help clinicians clearly and quickly identify or predict which drugs interact with CYP enzymes and cause clinically significant drug interactions. More research and clinical drug trials on these enzymes and their interactions need to be conducted and reported. With this in mind, one way to help manage these drug interactions is to have a basic understanding of the physiologic role CYP-450 enzymes play in metabolizing drugs. With knowledge of how these enzymes work and what their role is in drug interactions, pharmacists can better predict significant interactions that are likely to occur and identify potential problematic drugs.
An understanding of which CYP-450 isoenzyme is responsible for the metabolism of a drug is essential for trying to predict and understand the magnitude of drug interactions. Some drug-metabolism inhibitors are highly selective for certain CYP isoenzymes. 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 isoenzyme system, it is logical to assume that the new drug will exhibit drug interactions with known inducers and inhibitors of specific CYP isoenzymes. Management of patients in a clinical setting may be simplified if drugs that are known to produce harmful drug interactions with each other are avoided or at least limited and the patient is closely monitored.
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