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Update: clinically significant cytochrome p-450 drug interactions

Update: Clinically Significant Cytochrome P-450 Drug
Interactions
Elizabeth Landrum Michalets, Pharm.D.
Recent technologies have resulted in an explosion of information concerning
the cytochrome P-450 isoenzymes and increased awareness of life-threatening
interactions with such commonly prescribed drugs as cisapride and some
antihistamines. Knowledge of the substrates, inhibitors, and inducers of these
enzymes assists in predicting clinically significant drug interactions. In
addition to inhibition and induction, microsomal drug metabolism is affected
by genetic polymorphisms, age, nutrition, hepatic disease, and endogenous
chemicals. Of the more than 30 human isoenzymes identified to date, the
major ones responsible for drug metabolism include CYP3A4, CYP2D6,
CYP1A2, and the CYP2C subfamily.
(Pharmacotherapy 1998;18(1):84–112)
Significant Inhibitory Interactions: Protease Significant Induction Interactions: Protease Significant Induction Interactions: Estrogens and Significant Inhibitory Interactions: Antihistamines Significant Inhibitory Interactions: Cisapride Significant Inhibitory Interactions: Corticosteroids Significant Inhibitory Interactions: R-Warfarin Significant Inhibitory Interactions: Antidepressants Significant Induction Interactions: Benzodiazepines Significant Induction Interactions: Narcotic Significant Inhibitory Interactions: Cardiovascular Significant Inhibitory Interactions: Narcotic Significant Induction Interactions: Calcium Channel Significant Inhibitory Interactions: Theophylline Significant Induction Interactions: Theophylline Significant Inhibitory and Induction Reactions: Significant Inhibitory Interactions: R-Warfarin Significant Inhibitory Interactions: Antidepressants, Significant Induction Interactions: Benzodiazepines From the Department of Pharmacy, Mission–St. Joseph’s Health System, and the University of North Carolina School Significant Inhibitory Interactions: Phenytoin of Pharmacy Community-Based Practice, Asheville, North Significant Induction Interactions: Phenytoin Significant Inhibitory Interactions: S-Warfarin Address reprint requests to Elizabeth Landrum Michalets, Significant Induction Interactions: S-Warfarin Pharm.D., Department of Pharmacy, Mission–St. Joseph’sHealth System, 509 Biltmore Avenue, Asheville, NC 28801.
CYTOCHROME P-450 DRUG INTERACTIONS Michalets Nomenclature
one isoenzyme. For example, the pharmacologicallyactive enantiomer S-warfarin is metabolized by The cytochrome P (CYP)-450 isoenzymes are a group of heme-containing enzymes embedded primarily in the lipid bilayer of the endoplasmic systems.7, 8 Therefore, when one enzyme system reticulum of hepatocytes (Figure 1).1 Thesemetabolic enzymes are also present in high is inhibited or induced by an interacting drug, a concentrations in enterocytes of the small clinically significant interaction may or may not intestine, with smaller quantities in extrahepatic occur. Another example is tricyclic antidepressants, tissues (kidneys, lungs, brain). They are which are metabolized by CYP2D6, CYP1A2, and involved in oxidative metabolism (phase I) of a CYP3A4. Inhibition or genetic absence of one number of different drug classes as well as endo- isoenzyme can lead to compensation through the genous substances such as steroid hormones, secondary isoenzyme pathway. Similar to warfarin, fatty acids, and prostaglandins.2–4 The nomenclature oxidative metabolism can be preserved, and a first suggested by Nebert et al in 1987 and widely clinically significant interaction may or may not used today employs a three-tier classification consisting of the family (> 36% homology in In addition, a drug may inhibit or induce the amino acid sequence), subfamily (77% homology), activity of a specific isoenzyme even though it is not a substrate at that particular site. For example, Knowledge of the substrates, inhibitors, and quinidine is metabolized by the CYP3A4 enzyme, inducers of CYP-450 isoenzymes assists in but it is a potent inhibitor of CYP2D6.2, 10 predicting clinically significant drug interactions.
It is also important to recognize that genetic polymorphism in the functional expression of Inhibition most often occurs as a result of competitive binding at the enzyme’s binding site.
contributes to marked interpatient variability in Competitive inhibition depends on the affinity of drug metabolism, leading to poor metabolizers the substrate for the enzyme being inhibited, the (PMs) and extensive metabolizers (EMs).2, 3, 6 In addition to genetic influences, microsomal drug inhibition, and the half-life of the inhibitor drug.
metabolism is affected by age, nutrition, stress, The onset and offset of enzyme inhibition are dependent on the half-life and time to steady endogenous chemicals.1 Although more than 30 state of the inhibitor drug. For example, human CYP-450 isoenzymes have been identified to date, the major ones responsible for drug ingestion, and cimetidine (CYP1A2) inhibit drug metabolism are CYP3A4, CYP2D6, CYP1A2, and metabolism within 24 hours of a single dose, but amiodarone (CYP2C9) inhibitory interactionsmay not surface for months because of its long Substrates, Inhibition, and Induction
Some drugs may be metabolized by more than The time to maximum drug interaction (onset Figure 1. Cytochrome P-450 enzyme system. Reprinted by permission from Applied Pharmacokinetics: Principles of
Therapeutic Drug Monitoring, third edition, edited by WE Evans, JJ Schentag, and WJ Jusko, published by Applied
Therapeutics, Inc., Vancouver, WA,  1992.
PHARMACOTHERAPY Volume 18, Number 1, 1998 and termination) is also dependent on the time Both of these agents interact with warfarin required for the inhibited drug to reach a new metabolism. Whereas rifampin’s effects occur steady state.6, 12 For example, with the cimetidine- within 4 days, phenobarbital’s effects take 14–22 theophylline interaction, maximum increases in theophylline concentrations are not seen for A complicating factor is that the time course of approximately 2 days, since this time is required induction is also dependent on the time required for theophylline to reach a new steady state.13 production. In other words, the rate-limiting concentration-dependent half-life, steady-state factor may be the half-life of CYP450 enzyme changes in phenytoin serum concentration can turnover, which ranges from 1–6 days.17 Since take days to occur. Of interest, if the half-life of rifampin is eliminated more rapidly than the the inhibitor drug is shorter than that of the excess cytochrome enzymes, the rate-limiting inhibited drug, less time is required to revert to a factor in the duration of the interaction would be lower steady-state concentration after the enzyme turnover. With phenobarbital, accumu- inhibitor is stopped than is required to increase lation and elimination would be the rate-limiting to a new steady-state concentration when the factor in the onset and offset of induction.17 inhibitor is started. This is because the half-life Enzyme induction is also influenced by age of the affected drug is shorter after discontinuation and liver disease. The ability to induce drug metabolism may decrease with age, as evidenced by reports that drug metabolism in elderly subjects inhibition is noncompetitive, which can occur as (> 60 yrs) is not influenced by polycyclic aromatic a result of inhibitor inactivation of the enzyme hydrocarbons (PAH) in cigarette smoke, as it is in with normal substrate binding. The duration of younger subjects.1, 18 Also, patients with cirrhosis this type of inhibition may be longer if new or hepatitis may be less susceptible to enzyme enzymes are synthesized after the inhibitor drug Another contributing factor to the significance CYP3A4 Isoenzyme
of enzyme inhibition is the hepatic extraction The CYP3A4 isoenzyme is responsible for the ratio of the affected drug. In general, systemic metabolism of the widest range of drugs and clearance of low-extraction-ratio drugs is endogenous compounds in humans. It accounts expected to be affected to a greater extent than for 60% of cytochrome enzymes in the liver and that of high-extraction-ratio drugs. However, 70% of those in enterocytes found in the gut wall with high-extraction-ratio drugs with significant responsible for first-pass metabolism.2, 3, 17 No first pass metabolism, it is well known that evidence to date suggests the 3A4 isoenzyme significant changes in oral absorption can occur substrates, inhibitors, and inducers of CYP3A4are listed in Table 1.2, 3, 9, 10, 16, 17, 19–117 In recent years there has been an explosion of Enzyme induction, first recognized in the discussion about the 3A4 system because of life- threatening arrhythmic side effects that can occur increased or the synthesis of more CYP-450 as a result of enzyme inhibition and accumulationof the nonsedating antihistamines terfenadine and astemizole20–25 and cisapride.26–30 phenobarbital increases liver weight in a dose-dependent manner. In humans, liver biopsies inpatients taking anticonvulsants resulted in up to Significant Inhibitory Interactions: Antihistamines 52% larger absolute liver size.14 Like inhibitors, Terfenadine has been removed from the market inducers tend to be lipophilic, and the time because of its serious cardiovascular drug course of the interaction is dependent on the interactions. Its active carboxy metabolite, half-life of the inducer. For example, rifampin’s fexofenadine, is available and devoid of the fatal short half-life results in enzyme induction drug interactions.31 Astemizole undergoes (CYP3A4, CYP2C) apparent within 24 hours, extensive first-pass metabolism to active whereas phenobarbital’s longer half-life of 3–5 metabolites, and, like terfenadine, the parent days requires approximately 1 week for induction compound is the cardiotoxic entity.32 In many (CYP3A4, CYP1A2, CYP2C) to become apparent.
cases, drug interactions with terfenadine have CYTOCHROME P-450 DRUG INTERACTIONS Michalets Table 1. Cytochrome 3A4 Isoenzyme: Substrates, Inducers, and Inhibitors2, 3, 9, 10, 16, 17, 19–117
Substrates
been extrapolated to astemizole.31 Terfenadine, serious nature of potential drug interactions, available since 1985, was first reported in 1990 to cause QT prolongation and torsades de pointes candidiasis are not likely to present a problem.
when given together with ketoconazole.23 A The new antifungal terbinafine does not appear prospective study of six healthy volunteers given to inhibit the 3A4 system and is an alternative for the combination noted increased parent terfenadine concentrations and QT prolongation (mean 82- Erythromycin alone can cause QT prolongation,119 and when combined with terfenadine does so as In vitro, the ability of itraconazole, an anti- well (mean 10-msec increase) but to a lesser degree fungal similar to ketoconazole, to inhibit the 3A4 than when given with antifungal agents.20 This system is 10 times less potent than that of effect was also reported with clarithromycin31 but ketoconazole, but inhibitory differences in vivo not with azithromycin or dirithromycin, which are less impressive.33 Fluconazole also inhibits may be alternatives for patients receiving 3A4 in vitro, but did not increase parent terfenadine concentrations or cause arrhythmias In vitro evidence exists for inhibition of the at dosages of 200 mg/day.32 However, dosages 3A4 isoenzyme by the antidepressant drugs above 200 mg/day caused QT prolongation in sertraline. In addition, plasma concentrations of The antifungal agents itraconazole, ketoconazole, drugs metabolized by 3A4 such as carbamazepine fluconazole, and intravenous miconazole should and some benzodiazepines increased when given not be coadministered with astemizole due to the concomitantly with these four agents.9, 19, 39, 40 To PHARMACOTHERAPY Volume 18, Number 1, 1998 date, there are no in vitro data or case reports contraindicated with astemizole since the involving paroxetine in the inhibition of 3A4.19 combination may result in QT prolongation.58 It Data on significant drug interactions with these is prudent to limit the use of quinine and tonic antidepressants and antihistamines is less clear water in patients receiving astemizole.
than with antifungals and macrolides. Fluoxetine In vitro, the protease inhibitors saquinavir, caused arrhythmias in patients concomitantly ritonavir, indinavir, and nelfinavir inhibit cyto- receiving terfenadine.41, 42 Another concern with chrome 3A4.59 To date, neither pharmacokinetic fluoxetine is the long half-life of the parent studies nor in vivo drug-drug interaction studies compound (4–6 days) and its active metabolite have been conducted for these agents with norfluoxetine (4–16 days). The consequences of antihistamines. Prescribing information for an interaction may be minimized by delaying ritonavir60 lists concomitant administration with administration of astemizole for 2–4 weeks after astemizole as a contraindication, and prescribing discontinuing fluoxetine.43 Prescribing infor- information for saquinavir,61 indinavir,62 and mation for both fluvoxamine and nefazodone lists concomitant administration with astemizole concomitant astemizole administration because as a contraindication,44–46 and sertraline information of the potential for life-threatening cardiotoxic warns against concomitant administration with astemizole.47 Thus, fluoxetine, fluvoxamine, Other recommendations to minimize the risk nefazodone, and sertraline should be administered of cardiotoxic drug interactions include avoiding cautiously, if at all, to patients taking astemizole astemizole dosages greater than 10 mg/day, (Table 2).2, 3, 7–11, 14–118 In patients receiving prescribing alternative agents (Table 2), astemizole, alternatives for the treatment of prescribing astemizole cautiously in patients with depression are paroxetine19 and venlafaxine.48 The cardiac conditions that predispose them to QT tricyclic antidepressants should also be prescribed prolongation, administering the drug cautiously in cautiously since they can cause arrhythmias.9 patients taking other agents that can prolong the Fresh or frozen grapefruit juice inhibits QT interval (e.g., type Ia or III antiarrhythmics; inhibitory substance was once thought to be droperidol, tricyclic antidepressants), and naringenin, a human metabolite of nargingin.49–51 administering astemizole cautiously in patients However, the primary substance responsible for inhibition was identified in vitro to be a furano-coumarin compound widely found in nature, 6,7- Significant Inhibitory Interactions: Cisapride dihydroxybergamottin. This inhibitory substanceis less potent than ketoconazole but considerably The fact that cisapride can cause tachycardia, more active than cimetidine. Lack of 6,7- palpitations, and extrasystoles was first observed dihydroxybergamottin in orange juice probably in a review of records of over 13,000 patients receiving the agent.28 Postulations about the inhibitory effects.52–54 Inhibition of terfenadine cause of tachycardia include activation of metabolism with quantifiable levels of the serotonin-4 receptors on the myocardium63 and terfenadine parent compound, an increase in area prolonged atrioventricular conduction due to its under the curve (AUC) of 55%, and a mean QT structural similarity to procainamide.30 The first report of an arrhythmic drug interaction with patients ingesting grapefruit juice 240 ml cisapride was with erythromycin (for 2 days only) with dosages of cisapride that were rapidly twice/day.55, 56 Other studies reported similar escalated to 40 mg every 6 hours. The patient pharmacokinetic changes but associated with no developed a QT interval of 550 msec from a normal baseline with progression to polymorphic Recently the calcium channel blocker, mibefradil, nonsustained ventricular tachycardia. The QT has been shown to inhibit both CYP3A4 and interval returned to normal after the cisapride CYP2D6 and cause syncope in some patients taking dosage was decreased to 5 mg every 6 hours.29 ␤-blockers. Because mibefradil could theoretically Janssen Pharmaceutica continues to receive increase plasma concentrations of astemizole, its numerous reports of torsades de pointes, prolonged QT intervals, and deaths.27 Over 50% of these Another cytochrome 3A4 inhibitor is quinine.
patients were concomitantly receiving ketoconazole, At dosages greater than 430 mg/day, quinine is itraconazole, or fluconazole, and erythromycin, CYTOCHROME P-450 DRUG INTERACTIONS Michalets Table 2. 3A4 Clinically Significant Drug Interactions2–3, 7–11, 14–118
on starting or stopping; may alsobe 1A2 mediated.
dose related; monitor INR morecarefully.
tremor in some patients;monitor SC&E.
PHARMACOTHERAPY Volume 18, Number 1, 1998 Table 2. 3A4 Clinically Significant Drug Interactions2, 3, 7–11, 14–118 (continued)
clinical response reported;fluconazole less affected.
LoratadineaMetoclopramideaAzithromycinDirithromycin Ketoconazole (inh)Miconazole i.v. (inh)Fluoxetine (inh) Nefazodone (inh)Sertraline (inh)Grapefruit juice (inh) Nelfinavir (inh)Ritonavir (inh)Saquinavir (inh)Mibefradil (inh) 35% increase in terfenadineconc reported with zileuton.
monitoring; no cardiac sideeffects reported.
CYTOCHROME P-450 DRUG INTERACTIONS Michalets Table 2. 3A4 Clinically Significant Drug Interactions2, 3, 7–11, 14–118 (continued)
higher initial dosages ofbenzodiazepine.
Nelfinavir (inh)Ritonavir (inh)Saquinavir (inh)Rifampin (ind) increase; monitor clinicaleffects; best documentedwith diltiazem, verapamil,nifedipine.
PHARMACOTHERAPY Volume 18, Number 1, 1998 Table 2. 3A4 Clinically Significant Drug Interactions2, 3, 7–11, 14–118 (continued)
Erythromycin (inh)Cyclosporine (inh)Nifedipine (inh)Diltiazem (inh) Doxorubicin (inh)Etoposide (inh)Ketoconazole (inh)Erythromycin (inh) contraception for short courses;for long courses use higherdosages or medroxyprogesteroneacetate.
increase dosage to 50 µg estradiol.
Ritonavir (inh)Saquinavir (inh)Norfloxacin (inh) CYTOCHROME P-450 DRUG INTERACTIONS Michalets Table 2. 3A4 Clinically Significant Drug Interactions2, 3, 7–11, 14–118 (continued)
azole; monitor trough concmore carefully.
need dosage decrease;monitor trough conc.
53% with indinavir; decrease clarithromycin dosage by 50% for Clcr 30–60 ml/min and with rifampin and 50% with rifabutin;clinical significance unknown.
of icterus and uveitis; monitor forocular SE.
of icterus and uveitis; monitor forocular SE.
Ritonavir (inh)Saquinavir (inh)Rifampin (ind) PHARMACOTHERAPY Volume 18, Number 1, 1998 Table 2. 3A4 Clinically Significant Drug Interactions2–3, 7–11, 14–118 (continued)
ritonavir AUC 35%; may needdosage increase; see specificMMWR guidelines.
150%; with ketoconazole, decreaseinitial indinavir dosage to600 mg q8h; decreasesaquinavir dosage ifketoconazole dosage is> 200 mg/day.
SC&E = serum concentration and effects; INR = international normalized ratio; SE = side effects; CCB = calcium channel blockers; BP = bloodpressure; HR = heart rate; BMT = bone marrow transplantation; F = bioavailability; Clcr = creatinine clearance; MAC = Mycobacterium aviumintracellulare complex; AUC = area under the concentration-time curve.
aAlternative antihistamines and prokinetic agents in all interactions listed.
clarithromycin, or metronidazole. Risk factors at baseline to 440 msec, and he died from for arrhythmia were identified as history of ventricular fibrillation-cardiac arrest. The drug coronary disease and arrhythmia, renal insuf- interaction was postulated as a potential culprit.
ficiency, electrolyte imbalance, and long-term use Similar to antihistamines, only in vitro data about enzyme inhibition, and no actual patient- prolonged QT intervals such amiodarone and specific data, are the bases for contraindications and warnings against concomitant cisapride with Three reports in our institution in 1995–1996 other drugs such as fluvoxamine, mibefradil, involved fluconazole or erythromycin interactions nefazodone, sertraline, ritonavir, saquinavir, and with cisapride. Two patients were receiving both indinavir.38, 44–46, 60–62 It would also seem prudent fluconazole 100 and 400 mg/day and cisapride 20 to avoid administering fluoxetine, quinine, and mg every 6 hours, had no known cardiac disease, grapefruit juice with cisapride because of the fatal developed ventricular fibrillation, and had consequences of potential interactions, and resolution with no further arrhythmias after because similar interactions were documented cisapride was discontinued. One of these patients with terfenadine. As is the case with astemizole, initially had recurrence of sustained ventricular steps to minimize the cisapride drug interactions tachycardia after lidocaine was discontinued and include avoiding cisapride dosages greater than before cisapride was discontinued. The third 20 mg every 6 hours and exercising caution in patient had a history of cardiac disease and was patients with hepatic disease or other risk factors receiving erythromycin 500 mg intravenously every 6 hours plus oral cisapride 10 mg every 12 Hypoprothrombinemic effects of warfarin were hours. His QT interval increased from 352 msec CYTOCHROME P-450 DRUG INTERACTIONS Michalets cisapride. The patient’s international normalization diazepam and alprazolam, but enhancement of ratio (INR) at baseline was 2.2–2.5 and increased to 10.7, first noted 3 weeks after the patient Another antidepressant, nefazodone, increased began cisapride 10 mg 4 times/day. Competitive alprazolam plasma concentrations 2-fold and potentiated alprazolam-induced psychomotor postulated.69 The clinical significance of this impairment and sedation.71–74 Nefazodone also interaction remains to be established.
increased triazolam plasma concentrations andhalf-life by 1.7- and 3-fold, respectively.71–73 Significant Inhibitory Interactions: R-Warfarin Initial dosage reductions of alprazolam by 50%and triazolam by 75% should be made when Fluconazole, itraconazole, and ketoconazole adding nefazodone to existing therapy with these reportedly increase the anticoagulant effects ofwarfarin. Two-fold (fluconazole) and 3-fold (ketoconazole) increases in prothrombin time Grapefruit juice 200 ml increased peak plasma concentrations of orally administered midazolam by 56% and AUC by 52%. The clinical importance implicated to reduce the clearance of both Temazepam, although metabolized by the 3A4 Numerous reports describe enhancement of the system, does not result in significant pharmaco- hypoprothrombinemic effects of warfarin when kinetic or pharmacodynamic interactions as given in combination with erythromycin.
Prothrombin times increased up to 2-fold after 7 inhibitors such as erythromycin and itraconazole.76, 77 days of therapy, but there are few reports of Lack of interaction potential with temazepam bleeding complications. The clinical relevance of this interaction probably depends on many triazolam may be due to different metabolic patient factors including age, rate of warfarin pathways and lack of significant first-pass clearance, concurrent drug therapy, and ability to shunt to noninhibited pathways.33 The inter- reduced clearance of triazolam by 52% and action has not been observed with azithromycin, decreased midazolam clearance enough to cause but like erythromycin, caution is advised with unconsciousness. If it is not possible to avoid these combinations, the benzodiazepine dosage should be decreased by 50% and the patient similar to the imidazole ring of cimetidine and monitored carefully for respiratory depression has been studied for inhibitory drug interactions.
and other signs of toxicity.36 Inhibitors of 3A4 It inhibits the metabolism of R-warfarin, and this should therefore be administered with caution to interaction is likely to be 3A4 mediated. The patients taking alprazolam or triazolam and to effects appear after omeprazole has been taken those undergoing surgical procedures requiring for a few days, seem to be dose related, and do midazolam as a component of anesthesia.
not abate immediately on discontinuing the drug.
For the opioids, the only well-documented 3A4-mediated interaction is with alfentanil and patients receiving this combination. Lansoprazole erythromycin.70, 79 Reports include prolonged does not alter the clearance of warfarin and may respiratory depression associated with alfentanil in patients who were receiving erythromycinbefore surgery.70 Administration of cimetidine with fentanyl doubles the latter’s elimination half- life, thus potentially enhancing its pharmacologiceffects and duration of action.70 Alfentanil, alprazolam, midazolam, temazepam, and triazolam are among the currently known substrates of cytochrome 3A4.9, 19, 39, 40, 72 The benzodiazepines have fairly well documentedinteractions. Pharmacokinetic studies with Rifampin can significantly impair the efficacy alprazolam showed increased serum concentrations of some benzodiazepines. A 96% reduction in and prolonged half-life when given with the nonexistent hypnotic effects when administered Fluoxetine increased plasma concentrations of with rifampin to 10 healthy volunteers in a PHARMACOTHERAPY Volume 18, Number 1, 1998 double-blind crossover study.78 Similar results As mentioned, HMG-CoA reductase inhibitors were reported with triazolam and rifampin, with are metabolized by the 3A4 system and have markedly reduced effects of triazolam based on dose-related toxic effects on skeletal muscle that may range from diffuse myalgia and myopathy to Like benzodiazepines, it is well known that rifampin increases the rate of metabolism of reported most frequently with lovastatin but have also been reported rarely with the other statins.87, greatest when HMG-CoA reductase inhibitors are combined with 3A4 inhibitor drugs or agents that compete with 3A4 metabolism.89–94 This inter-action has been well described with cyclosporine, and less often with gemfibrozil and niacin.89 dependent on the 3A4 isoenzyme system for In a double-blind, crossover trial, itraconazole metabolism. Other cardiovascular drugs metab- increased lovastatin peak concentrations by 20- olized by 3A4 are the hydroxymethylglutaryl- fold in 12 healthy volunteers. Side effects were not reported in any subjects except one who Grapefruit juice 200–250 ml given before drug experienced a 10-fold increase in creatine administration increased the AUC of felodipine kinase.90 Reports of severe rhabdomyolysis by 185%, with an average increase of 240%.
occurring after the addition of itraconazole to Similar results occurred with nifedipine, nimodipine, lovastatin and niacin therapy underscore the and verapamil but not with diltiazem.50, 55 potential harm of these interactions. Myopathy Furthermore, this pharmacokinetic interaction also occurred after itraconazole was added to was clinically significant, with lower diastolic cyclosporine and simvastatin therapy in a blood pressure, higher heart rate, and more frequent vasodilation-related side effects with described the development of rhabdomyolysis felodipine, nisoldipine (5-fold increase in AUC), when lovastatin was combined with erythromycin.
and nifedipine.55, 80, 81 This information supports Myopathy is quickly reversible when the statin is cautioning patients about concomitant ingestion of grapefruit juice and calcium antagonists.
Concomitant administration of ritonavir and A patient taking oral felodipine 10 mg/day was lovastatin increased the AUC of lovastatin by 3- given oral erythromycin 250 mg twice/day and fold. Little information is available about developed flushing, ankle and leg edema, and protease inhibitors, but careful dosing with tachycardia. When erythromycin was discon- statins is prudent.58, 60–62 Giving statins with 3A4 tinued, felodipine levels were reduced from 6 to inhibitors should be avoided or dosages of statins less than 2 nmol/L and symptoms resolved.82 On reduced to avoid the potential for rhabdomyolysis.
average, it appears that erythromycin increases Patients should be instructed to monitor for signs felodipine concentrations by 3-fold.55 Other of myopathy such as muscular pain, tenderness, studies have demonstrated similar increases in or weakness, and plasma creatine kinase should felodipine concentrations when given with erythromycin.83 Other reports documentedsubstantial peripheral edema and/or elevated Significant Induction Interactions: Calcium calcium antagonist serum concentrations during concurrent administration of itraconazole withfelodipine, isradipine, or nifedipine.84–86 An 8- In one study, enzyme induction with rifampin fold increase in feldopine’s AUC was seen when resulted in up to a 32-fold increase in verapamil the agent was given with itraconazole 200 clearance and a 25-fold decrease in verapamil mg/day, and was associated with statistically bioavailability after oral administration.95 The significant changes in systolic and diastolic blood effect of oral verapamil on atrioventricular conduction was nearly abolished with rifampin If concurrent therapy of potent 3A4 inhibitors administration, and the authors concluded that with calcium antagonists is required, the patient prehepatic metabolism of verapamil was induced should be monitored for signs of toxicity and the by rifampin. Rifampin is expected to have a dosage of calcium channel blocker decreased, if similar reaction with other calcium channel CYTOCHROME P-450 DRUG INTERACTIONS Michalets rifampin, carbamazepine, phenobarbital, andphenytoin are postulated to enhance efficacy and Quinidine is known to be a cytochrome 2D6 toxicity through 3A4 activation. In immuno- inhibitor but is metabolized by the 3A4 system.
histochemical studies, some patients with Cytochrome 3A4 interactions that are well pulmonary carcinoma showed expression of the documented include those with cimetidine,2, 13 3A4 enzyme, and studies are continuing to assess phenytoin, phenobarbital,2, 120 and rifampin.2, 114 if this presence leads to local activation and a Of interest, metronidazole is a 3A4 inhibitor due to its interaction with cisapride,27 and a potential In contrast, inhibitors and other substrates of interaction of quinidine with either metronidazole 3A4, such as ketoconazole, itraconazole, diltiazem, verapamil, and cyclosporine, could possibly difference in quinidine trough concentrations interfere with activation and efficacy of was noted, but with no changes in the patient’s ifosfamide The clinical significance of inhibition QT interval.10 An interaction with metronidazole seems more likely since it is a known 3A4 In vitro, vinblastine metabolism is inhibited by inhibitor. Quinidine concentrations should be other anticancer drugs, including doxorubicin monitored and patients assessed for signs of and etoposide, together with more familiar inhibitors, ketoconazole and erythromycin.
Although not studied clinically, these interactions Significant Inhibitory and Induction Reactions: may alter the antitumor activity and/or toxicity of vinblastine.101 Concomitant treatment with Little is known about pharmacokinetic inter- actions with chemotherapeutic agents, but it is nifedipine resulted in a 4-fold increase in likely that important interactions have not been vincristine's elimination half-life. Clinical studies identified. The 3A4 enzyme was important in the are necessary to validate the pharmacokinetic data, but greater cytotoxicity could be anticipated.102 epipodophylotoxins, tamoxifen, ifosfamide, Busulfan is another chemotherapeutic agent paclitaxel, and vinca alkaloids. Although beyond that may be metabolized through the 3A4 system.
the scope of this review, it is interesting to note A study in 13 bone marrow transplant recipients that 3A4 catalyzes the activation of the prodrug found an average 20% reduction in busulfan ifosfamide, raising the possibility that it could be clearance in patients receiving itraconazole activated in tumor tissues containing this enzyme.
compared with those receiving either fluconazole Cytochrome 3A4 substrates may also modulate or placebo. Itraconazole is known to be a more multidrug resistance to cancer chemotherapy.97 potent inhibitor of 3A4 than fluconazole.34 The Cyclosporine increased the AUC of doxorubicin nature of this interaction has yet to be elucidated, by 55% and decreased doxorubicin clearance by but inhibition of oxidative metabolism may be a 50%. The addition of cyclosporine also increased doxorubicin-induced nausea and vomiting.
Similar myelosuppression was observed when administered concurrently with inducers such comparing doxorubicin alone with doxorubicin phenobarbital and phenytoin, with a mean 170% (60% of the control dose) plus cyclosporine.98 increase in clearance reported with these drugs.
Similar pharmacokinetic results were obtained On the other hand, concurrent administration and a higher frequency of drug-related toxicity with cyclosporine resulted in an 80% increase in was observed in patients receiving cyclosporine.99 AUC and a 2-fold increase in etoposide half-life.97 Simultaneous administration of doxorubicin and In vitro, tamoxifen metabolism is inhibited by paclitaxel also resulted in significantly elevated erythromycin, cyclosporine, nifedipine, and concentrations of doxorubicin, suggesting that diltiazem. No clinical data are available, but paclitaxel may inhibit its metabolism.100 interactions are likely to occur and should be Ifosfamide is an alkylating agent that requires biotransformation to produce its pharmacologically active cytoxic compound. This activation by the 3A4 system also results in the formation of a chemotherapeutic agents. However, significant interactions with cytochrome 3A4 inhibitors or metabolite by N-dechlorethylation. Few studies inducers are likely to become more apparent in PHARMACOTHERAPY Volume 18, Number 1, 1998 Table 3. Cytochrome 2D6 Isoenzyme: Substrates, Inducers, and Inhibitors2, 3, 9, 16, 19, 33, 43, 48, 58, 60, 70, 96, 114, 120–125
Substrates
Significant Inhibitory Interactions: Protease interactions with these agents, but the potential for interactions has been addressed based onpharmacokinetic in vitro data.108 The majority of As previously described, protease inhibitors these data are with ritonavir, but prescribers saquinavir, ritonavir, indinavir, and nelfinavir are should be aware that concomitant administration substrates and inhibitors of the cytochrome 3A4 of drugs metabolized by the 3A4 system with system. Ritonavir is also a significant inhibitor of other protease inhibitors may also result in the 2D6 isoenzyme system (Table 3).2, 3, 9, 16, 19, 33, inhibitor ketoconazole with indinavir should combination with nucleosides and several other include a dosage reduction of indinavir to 600 drugs (e.g., antimicrobials, antivirals) used to mg every 8 hours.62 Ketoconazole increases the treat infections in patients with the acquired AUC of saquinavir by 150%, but the consistency immunodeficiency syndrome. When comparing and extent of this interaction varies widely these agents, ritonavir appears to be a more among patients.125 Generally, when given in potent inhibitor, and patients receiving it will combination with saquinavir, dosage adjustment require additional monitoring to avoid significant is not required unless ketoconazole dosages interactions. Indinavir appears to less potent and is a reversible inhibitor of 3A4.125 Therefore, it Fluconazole's effect on protease inhibitor may be rational to give ritonavir in the early stage concentrations is unknown, but it may not of human immunodeficiency virus (HIV) disease before a patient begins receiving numerous drugs concentrations as the addition of ketoconazole that may interact and require complex dosage because it is not thought to be as potent of an inhibitor.125 Similarly, concomitant administration Due to the poor absorption of saquinavir, it has of fluconazole 200 mg/day and ritonavir 200 mg been studied in combination with ritonavir to 4 times/day resulted in insignificant changes in increase its plasma concentrations. Ritonavir has the half-life of ritonavir. Dosage adjustments are increased saquinavir concentrations by 18-fold.125 This concept of combination therapy with other protease inhibitors warrants further study.
concentrations by inhibiting 3A4 metabolism.
Occupational exposure to HIV may now result Ritonavir and nelfinavir increase the rifabutin in a 4-week course of indinavir or other protease AUC by 4-fold and 207%, respectively.63–65 These inhibitor.105 Little clinical information and few increases are associated with an increased risk of case reports are available regarding drug side effects including uveitis, making the CYTOCHROME P-450 DRUG INTERACTIONS Michalets Table 4. 2D6 Clinically Significant Drug Interactions2, 3, 9, 16, 19, 33, 38, 43, 48, 58, 60, 70, 96, 114, 120–130
analgesic effects; higher riskin PMs and EMs taking inhibitors;reduced morphine conc by 95%.
in serum conc with QRSprolongation; monitor ECG.
Chronic ETOH ingestion (ind)Acute ETOH ingestion (inh) PHARMACOTHERAPY Volume 18, Number 1, 1998 Table 4. 2D6 Clinically Significant Drug Interactions2, 3, 9, 16, 19, 33, 38, 43, 48, 58, 60, 70, 96, 114, 120–130 (continued)
DesipramineImipramineMaprotilineNortriptyline haloperidol; monitor for side effects.
PMs = poor metabolizers; EMs = extensive metabolizers; AUC = area under the concentration-time curve; SE = side effects; PAH = polycyclicaromatic hydrocarbons; TCA = tricyclic antidepressant.
combination contraindicated.125 Concomitant administration of indinavir with rifabutin led to Benzodiazepines and opiates have demonstrated a 204% increase in rifabutin AUC. Therefore, an reduced clearance when given in combination adjustment to one-half the standard rifabutin with ritonavir and indinavir. If used in combi- dosage is recommended for patients receiving nation with protease inhibitors, dosages should this combination.62, 125 Of note, a similar be reduced or alternative agents should be interaction was observed between rifabutin and fluconazole, making monitoring for ocular side CYTOCHROME P-450 DRUG INTERACTIONS Michalets ritonavir and noted to have a significant (> 3-fold) Table 5. Cytochrome 1A2 Isoenzyme: Substrates,
increase in their AUC include benzodiazepines, Inducers, and Inhibitors2, 3, 9, 16, 18, 36, 37, 39, 40, 45, 96, 114, 117, 120,
131–139

calcium channel blockers, antidepressants,antiarrhythmics, corticosteroids, anticoagulants, and opiates.125 Ritonavir increased the AUC of many 2D6-metabolized drugs by 1.5- to 3-fold (Table 4),2, 3, 9, 16, 19, 33, 43, 48, 58, 60, 70, 114, 120–130 together with changes in some 1A2-metabolized drugs (Table 5).2, 3, 9, 16, 18, 36, 37, 39, 40, 45, 96, 114, 117, 120, 131–139 Large dosage adjustments (50% reduction) may Ritonavir caused a 77% increase in the AUC of clarithromycin. Prescribing information for ritonavir recommends no dosage adjustment in patients with normal renal function, a 50% reduction in clarithromycin dosage in patients with creatinine clearance (Clcr) of 30–60 ml/minute, and a 75% reduction for Clcr below 30 ml/minute. Another specific example of an AUC increase associated with ritonavir is PAH = polycyclic aromatic hydrocarbons.
Desipramine dosages should be decreased whenthe drug is given concurrently with ritonavir.60 cautiously in combination with drugs primarily discontinued during rifampin therapy, two options are available. The first is to administer a metabolized by the 2D6 system (ritonavir only).
four-drug tuberculosis regimen that includes rifampin for a minimum of 2 months or until accompanied by careful clinical monitoring for side effects and dosage adjustments is some achieved. Rifampin can be discontinued and a modified regimen continued for 16 additionalmonths after that time. This option cannot be Significant Induction Interactions: Protease attempted in isoniazid-resistant patients. Option 2 is to continue protease inhibitor therapy withindinavir 800 mg every 8 hours, or switch to One major interaction of concern with these indinavir if the patient is taking another protease drugs is rifampin's and rifabutin's induction of inhibitor, and administer a four-drug, 9-month metabolism. Rifampin 300–600 mg/day decreased regimen that contains rifabutin 150 mg/day (one- half usual dosage) instead of rifampin. This is saquinavir dosage adjustments necessary.
based on the fact that rifabutin has less inducing Rifampin decreased the maximum concentration respectively.125 Rifabutin is a less potent inducer Other agents that are known inducers of 3A4, than rifampin, but decreased saquinavir plasma including phenobarbital, phenytoin, carbamazepine, concentrations by 40%.61, 125 The clinical and dexamethasone, should be given cautiously significance of these decreases in protease with these drugs; alternatives are recommended, inhibitor concentrations is unknown, but given if possible.125 Tobacco, another known inducer, the fact that resistance is associated with is associated with an 18% decrease in the AUC of ritonavir.60 Specific dosage adjustments in Guidelines for concomitant administration of rifampin with protease inhibitors were published recently by the Centers for Disease Control andPrevention in the Morbidity and Mortality Weekly Numerous drug interactions with cyclosporine Report.59 If protease inhibitor therapy cannot be have surfaced in recent years that are associated PHARMACOTHERAPY Volume 18, Number 1, 1998 with its metabolism and presystemic metabolism a higher-dose oral contraceptive (50 µg ethinyl by the 3A4 enzyme in the liver and intestine, estradiol), medroxyprogesterone, or nonhormonal respectively. It is postulated that gastrointestinal alternative method of contraception is desirable.
tract metabolism may in part explain its erratic Similarly, corticosteroid clearance is increased absorption.107–109 In fact, 3A4 inhibition has been with the same concomitant agents. Patients given intentionally to improve cyclosporine's receiving corticosteroids for chronic diseases requirements. Ketoconazole 200–400 mg/day can decrease dosage requirements by 60–80%.
Serum concentrations begin to increase within 2 benzodiazepines, which also may compete with days, but 2–4 weeks may be required for or induce microsomal hepatic enzymes. They may reduce the effectiveness of oral contraceptives, whereas oral contraceptives can enhance the cyclosporine dosage requirements by as much as effect of benzodiazepines by competing with 30%.112 In some studies, grapefruit juice increased the drug's AUC by 19–60% when given benzodiazepines, an alternative method of within 90 minutes before or after cyclosporine.52, contraception is desirable. Oral contraceptives However, other authors showed no change in themselves reduce prednisolone clearance up to cyclosporine AUC or trough concentrations with 50%, increase serum phenytoin concentrations, concomitant administration of grapefruit juice decrease metoprolol clearance, and reduce 1.5 L/day.55 Therefore, the effect with grapefruit juice is highly variable, and the clinical clinically significant these interactions are A study in pediatric renal transplant recipients showed that lower dosages of cyclosporine are Significant Inhibitory Interactions: Corticosteroids required in patients also receiving norfloxacin.
Little information is available regarding This has not been seen with ciprofloxacin.113 inhibition of estrogen or corticosteroid metabolism.
Other drugs that alter cyclosporine concen- trations secondary to cytochrome 3A4 inhibition prednisolone and methylprednisolone in humans include verapamil, nicardipine,107–109 fluconazole, through inhibition of metabolism. Further itraconazole, ketoconazole, erythromycin, studies are required to clarify the clinical clarithromycin,33, 108, 109 tacrolimus,108, 109 and mibefradil.38 Cyclosporine concentrations aredecreased secondary to enzyme induction with 2D6 Isoenzyme
rifampin,16, 33, 108, 109, 114 phenytoin, carbamazepine,and phenobarbital.108, 109,120 Cyclosporine trough identified over 15 years ago. Administration of discontinued in combination with cyclosporine.
dextromethorphan followed by measurement ofO-demethylated metabolite excretion in urine is Significant Induction Interactions: Estrogens and an accurate and noninvasive way of phenotyping individuals as either EMs or PMs for 2D6 activity.
The PMs lack this enzyme as a result of an autosomal recessively transmitted defect in its unintended pregnancies due to drug interactions expression. Of note, approximately 5–10% of are increasing, perhaps due to the fact that estrogen whites are PMs compared with 1–3% of African- and progestin concentrations of oral contraceptives are decreased. Clinically significant drug interactions with oral contraceptives secondary clearance to an inactive metabolite by 2D6, PMs to 3A4 enzyme induction include carbamazepine, may have a larger response and be at greater risk of toxicity than EMs. For example, there is an primidone, and rifampin,114, 115, 117, 120 They have not been reported with gabapentin, lamotrigine, antidepressant-induced cardiotoxicity and with topiramate, and valproate. With these interactions, neuroleptic-induced side effects.19 Furthermore, CYTOCHROME P-450 DRUG INTERACTIONS Michalets inhibition can reduce the metabolic rate in an warranted (Table 4).2, 3, 9, 16, 19, 33, 38, 43, 48, 58, 60, 70, 114, EM to a value comparable with that of a PM.2, 5, 9, trazodone, with serotonergic syndrome occurring metabolite by 2D6 (e.g., conversion of codeine to with 24 hours of administration of paroxetine 20 morphine), the drug may be ineffective in PMs.
Induction cannot convert PMs to EMs, because We encountered a potential drug interaction in only inactive or relatively inactive forms of the our institution that may have been mediated partly by fluoxetine inhibition of the 2D6 system.
A 59-year-old woman was admitted for Achilles identified,21, 9 but significant interactions between tendon repair. Her baseline QT interval on 2D6-metabolized drugs with the well-known admission was prolonged (497 msec). Her drugs inducers rifampin114 and anticonvulsants120 have before admission included cyclobenzaprine, Large numbers of drugs affecting the cardio- triamterene-hydrochlorothiazide. She had no vascular and central nervous systems have been known history of cardiac disorders except for identified as substrates for 2D6 (Table 3).2, 9, 39, 40, hypertension. During outpatient surgery she had sudden onset of torsades de pointes thatdeteriorated into ventricular fibrillation.
Preoperatively, she received droperidol, which is known to potentiate QT prolongation and shouldbe given cautiously to patients with baseline QT In vivo, the selective serotonin reuptake inhibitor (SSRI) antidepressants fluoxetine and normal sinus rhythm with magnesium sulfate paroxetine are equipotent inhibitors of 2D6.
and defibrillation. All drugs were discontinued, Sertraline has less pronounced inhibition, and and her QT interval returned to below baseline fluvoxamine is almost devoid of inhibitory levels by postoperative day 1. The question effects.9, 122, 132 Coadministration with tricyclic remained about the etiology of her baseline QT antidepressants (TCAs) has been a focus of prolongation; we postulated inhibition of interest since these drugs are coadministered in cyclobenzaprine metabolism by fluoxetine.
some cases for resistant patients. Administration Cyclobenzaprine is hepatically metabolized, of desipramine with fluoxetine 20 mg/day and has a structure similar to TCAs (2D6, 3A4, 1A2 paroxetine 20 mg/day produced up to 4-and 3- metabolized),96 and caused conduction abnormalities fold increases, respectively, in peak serum in cases of overdose. In addition, its average half- concentrations. Similar results were shown with life is 24 hours, which corresponds to the gradual nortriptyline and imipramine.9 This inhibition decrease in the patient’s QT interval.127 Fluoxetine is reversed within 1 week of discontinuing is a known inhibitor of 2D6, 3A4, and 2C, and paroxetine, 1–2 weeks with sertraline, and up to reportedly increases serum concentrations of 5 weeks with fluoxetine because of the prolonged TCAs due to these effects.9, 19, 122–124 Although not half-lives of the parent compound and its documented, the potential exists for inhibition of cyclobenzaprine metabolism by fluoxetine.
On average, the percentage increase in TCA Interactions secondary to enzyme inhibition by plasma concentrations over baseline has ranged SSRIs and that are documented by pharmaco- from 58–150% with sertraline 50 mg/day and kinetic studies and case reports occurred with 110–375% with fluoxetine 20 mg/day.19 Clinical flecainide, propafenone, haloperidol, and other sequelae resulting from the coadministration of antipsychotics. Due to the narrow therapeutic SSRIs and TCAs have been reported only rarely, index and high-risk patients who receive type Ic but full dosages of both agents could clearly lead antiarrhythmics, SSRIs should be avoided in to plasma concentrations in the toxic range. A patients taking these drugs.19 Vigilant pharmaco- summary of 25 cases involving combinations of dynamic monitoring should accompany therapy fluoxetine and various TCAs showed that the with SSRIs in patients treated with other drugs magnitude of increased TCA concentrations is variable, does not correlate with the occurrence of adverse effects, and is not predictable.124 identified as a 2D6 substrate or inhibitor, a report Lower dosages with these combinations along with careful monitoring for side effects seem receiving long-term fluoxetine 80 mg/day and PHARMACOTHERAPY Volume 18, Number 1, 1998 clarithromycin indicates this potential. The effect is achievable. Codeine is a prodrug and patient’s delirium quickly cleared after he stopped 10% of the dose is O-demethylated to the active the drugs, and did not recur with erythromycin metabolite, morphine. This demethylation is alone or when he restarted fluoxetine 80 mg/day.
impaired in PMs and reduced in EMs during The authors concluded that the delirium was treatment with inhibitor drugs.3 The combination consistent with fluoxetine intoxication, which should probably be avoided since diminution of codeine’s effect is is highly probable.
Other potential interactions with TCAs include 1A2 Isoenzyme
mibefradil and quinidine. Quinidine is the mostpotent 2D6 inhibitor identified to date.39 It The 1A2 isoenzyme is of clinical interest inhibited TCA metabolism and resulted in 85% because of the large number of drug interactions reduction in desipramine clearance and a 35% associated with theophylline dealkylation and decrease in imipramine clearance.129 Mibefradil because of its inducibility by PAH in cigarette is a CYP2D6 inhibitor and can increase plasma smoke and charcoal-broiled foods. No genetic levels of TCAs, necessitating substantial dosage polymorphism has been defined but possibly reductions.38 Patients receiving these combinations exists because of observations of a trimodal should be monitored for signs of TCA toxicity.
pattern of caffeine metabolism. The 1A2 enzymeis also responsible for metabolism of the R- Significant Induction Interactions: Narcotic isomer of warfarin as well as with severalbenzodiazepines. As noted in Table 5,2, 3, 9, 16, 18, 36, 37, 39, 40, 45, 96, 114, 117, 120, 131–139 drugs known to be inhibitors of 1A2 include fluvoxamine (very methadone, and morphine are metabolized by potent),2, 19, 39, 132 cimetidine,13, 131 macrolides,36, 37, 131 and several of the quinolones.131,134–136 interactions result from enzyme induction andloss of opioid activity.70 Rifampin 600–900 Significant Inhibitory Interactions: Theophylline mg/day precipitated withdrawal symptoms whengiven to 21 patients with tuberculosis receiving Cimetidine is an enzyme inhibitor and causes a methadone maintenance.130 Similar effects were pharmacokinetic interaction with theophylline (theophylline clearance is decreased approximately Consideration should be given to opioid dosage 30%). Pharmacodynamic data are lacking, however.
increases when rifampin is begun, and patients An initial dosage reduction should be considered should be monitored closely for symptoms of in patients with a baseline theophylline level withdrawal. Similar enzyme-inducing effects and above 12 µg/ml due to theophylline's narrow signs of narcotic withdrawal with up to 50% reduction in methadone concentrations were Fluvoxamine is a potent inhibitor of 1A2, unlike the other SSRIs. It increased theophylline phenobarbital, and carbamazepine. Pharmaco- concentrations 2- to 3-fold, along with significant kinetic studies also indicated that reductions in increases in haloperidol and clozapine concen- the clearance of meperidine could be expected trations.19, 132 The majority of patients had with these enzyme-inducing agents.70, 120 increased plasma theophylline concentrations Pharmacodynamic monitoring would appear to be the most appropriate management strategy Interactions with macrolides are fairly well when narcotics are given concurrently with documented. In most studies, erythromycin and enzyme-inducing agents.2, 3, 9, 16, 19, 33, 43, 48, 58, 60, 70, clarithromycin decreased theophylline clearance 20–25% after 7 days of concomitant adminis-tration. Most clinicians recommend theophylline Significant Inhibitory Interactions: Narcotic dosage reduction and careful monitoring if thebaseline theophylline level is above 12 µg/ml.
Other macrolides such as azithromycin and Coadministration of cimetidine 1200 mg/day with meperidine decreased meperidine clearance alternatives.36, 37,131 In one patient, however, addition of azithromycin to a maintenance Special care should be taken when administering theophylline regimen resulted in an increase in codeine with 2D6 inhibitors or when no clinical serum concentration from the usual 12.7–15.5 CYTOCHROME P-450 DRUG INTERACTIONS Michalets µg/ml to 20 µg/ml, and discontinuation of several of these drug interactions have been azithromycin resulted in a 80% decrease in the concentration. This was confirmed with two A series of case reports described the inter- rechallenges.132 Thus, clinicians should be aware action between warfarin and quinolones that can of the potential for an interaction with azithromycin.
occur as early as day 2 or as late as day 16 after Several quinolones commonly decrease theo- phylline clearance. Enoxacin has the greatest complications attributed to this interaction have potential, with a 50–65% reduction in clearance, been reported as well. Ciprofloxacin, norfloxacin, followed by ciprofloxacin with a 25–30% decrease ofloxacin (least likely), nalidixic acid, and and norfloxacin with a 10–15% decrease.75, enoxacin were implicated in these reports.
131,134–136 These interactions resulted in symptoms According to pharmacokinetic studies, the of theophylline toxicity including seizures. Up to interaction is probably secondary to inhibition of the R-stereoisomer of warfarin, which is partly patients with a baseline theophylline level above metabolized by the 1A2 isoenzyme.33, 135, 136 12 µg/ml when beginning these combinations.129, However, several prospective, placebo-controlled trials showed no clinically significant effect.138, 139 ofloxacin, levofloxacin, lomefloxacin, and spar- Since warfarin is metabolized by enzymes from floxacin are unusual, making them alternative three different families, most individuals may be able to shunt its metabolism to a noninhibited Isoniazid also decreases theophylline clearance pathway. Although this interaction may be rare after at least 6 days of concomitant administration.
and unpredictable, careful monitoring of the INR This appears to be most pronounced in slow is warranted during concomitant therapy (Table acetylators, with up to a 2-fold increase in theo- 6).2, 3, 9, 16, 18, 36, 37, 39, 40, 45, 114, 117, 120, 131–139 Alternative quinolones with little to no inhibitory properties Oral contraceptives decrease theophylline include levofloxacin, lomefloxacin, and sparfloxacin.
clearance by 30%, necessitating more careful The manufacturer of fluvoxamine has received monitoring when starting or discontinuing 11 reports of interactions with warfarin. The concomitant therapy with theophylline. The drug increases the measured warfarin concen- proposed mechanism is inhibition of metabolism.117 trations by 65%; all patients in case reports had Grapefruit juice has no effect on theophylline metabolism, although it may have some 1A2 bleeding complications.132 The safety of combining warfarin with other SSRIs was studied in patientspreviously maintained with warfarin. Fluoxetine Significant Induction Interactions: Theophylline appears to have no effect, and both paroxetine and sertraline caused an increase in prothrombin enzymes responsible for theophylline metabolism.
time, with reports of minor bleeding with It was estimated that smokers may require up to twice the dosage relative to that of nonsmokers, warranted during therapy with any SSRI.
and a dosage reduction by one-fourth to one- Warfarin metabolism is known to be inhibited third during abstinence. Some reports indicate by cimetidine, but data on pharmacodynamic and that enzyme induction is present for up to several clinical effects are lacking. It seems prudent to monitor the INR carefully during combination Other well-established induction interactions therapy or to consider an alternative histamine2 with theophylline including rifampin and the (H2) antagonist.13 The enzyme-inhibitory effects anticonvulsant drugs carbamazepine, pheno- of cimetidine are attributed to its imidazole ring.
barbital, and phenytoin114, 120, 131 are summarizedin Table 6.2, 3, 9, 16, 18, 36, 37, 39, 40, 45, 114, 117, 120, 131–139 Significant Inhibitory Interactions:Antidepressants, Antipsychotics, and Significant Inhibitory Interactions: R-Warfarin As discussed, the R-isomer of warfarin is the Fluvoxamine increases plasma concentrations with clinical symptoms of toxicity (e.g., confusion, significant drug interactions have resulted from tremor, extrapyramidal syndrome) in patients inhibition of its metabolism. The R-isomer is receiving amitriptyline (2-fold increase), partially metabolized by the 3A4 system, and clomipramine (8-fold), clozapine (3.2- to 11.8- PHARMACOTHERAPY Volume 18, Number 1, 1998 Table 6. 1A2 Clinically Significant Drug Interactions2, 3, 9, 16, 18, 36, 37, 39, 40, 45, 114, 117, 120, 131–139
need initial dosage increase;monitor serum conc.
more careful monitoring ifbaseline level ≥ 12 µg/ml.
increased theophylline dosage maybe required; monitor serum conc.
conc; more pronounced in slowacetylators; monitor serum conc.
significant if > 35 µg estrogen.
monitor serum conc; effects maypersist for 3 mo after smokingcessation.
Fluoxetine (inh)Paroxetine (inh)Sertraline (inh)Zileuton (inh) CYTOCHROME P-450 DRUG INTERACTIONS Michalets Table 6. 1A2 Clinically Significant Drug Interactions2, 3, 9, 16, 18, 36, 37, 39, 40, 45, 114, 117, 120, 131–139 (continued)
AUC = area under the concentration-time curve; SC&E = serum concentration and effects; INR = international normalized ratio; PAH =polycyclic aromatic hydrocarbons; EPS = extrapyramidal syndrome.
fold), desipramine (1-fold), and imipramine (1.3- metabolized by this subfamily.19, 130 In addition, to 5.7-fold).132 Patients receiving these combi- as noted in Table 7,2, 13, 65–68, 120, 132, 140–143 chlor- nations should be monitored for side effects and amphenicol,33, 120 cimetidine,13, 120 and isoniazid16, 120 are probable inhibitors on the basis ofsignificant interactions with phenytoin.
Significant Induction Interactions:Benzodiazepines Significant Inhibitory Interactions: Phenytoin Similar to theophylline, the inducing effects of Case reports of 26 patients with steady-state smoking are associated with less drowsiness in phenytoin concentrations described a 67–309% patients taking chlordiazepoxide and diazepam.
increase in serum concentrations with the This was studied in a comprehensive in-hospital addition of the inhibitor fluoxetine within 5–13 days. Symptoms of toxicity occurred.19 Fluvoxamine, nonsmokers, light smokers, and heavy smokers receiving these benzodiazepines. Smokers mayrequire larger dosages of benzodiazepines toachieve a sedative or anxiolytic effect.18 Table 7. Cytochrome 2C Isoenzyme: Substrates,
Inducers, and Inhibitors2, 13, 16, 33, 65–68, 120, 132, 140–143

2C Isoenzyme
The 2C subfamily consists of isoenzymes 2C9, exhibits genetic polymorphism, with 20% of Asians and African-Americans and 3–5% of Caucasians reported as PMs.2, 19 Drugs meta- bolized by the 2C subfamily include phenytoin (2C9), S-warfarin (2C9), and omeprazole.
Diazepam, clomipramine, amitriptyline, and imipramine are demethylated by 2C enzymes.
amiodarone (2C9) and omeprazole (2C19).
Fluvoxamine, fluoxetine, and sertraline may inhibit these enzymes on the basis of increases in plasma concentrations of drugs believed to be PHARMACOTHERAPY Volume 18, Number 1, 1998 Table 8. 2C Clinically Significant Drug Interactions2, 11, 13, 15, 16, 19, 33, 65–68, 120, 132, 140–143
carefully when starting andstopping therapy.
carefully; more pronounced inslow acetylators; monitor forataxia, nystagmus, drowsiness.
monitor SC&E; adjust dosagesas necessary.
monitor serum conc carefullyor give alternative.
conc after 14 days; monitor levelscarefully.
within 3–4 weeks; reducedosage based on serum conc.
nausea, vomiting, vertigo; avoidif possible.
decrease dosage 25% whenstarting therapy.
SC&E = serum concentration and effects; INR = international normalized ratio; PT = prothrombin time; SE = side effects.
CYTOCHROME P-450 DRUG INTERACTIONS Michalets interaction can be seen from 1 week to 2 months inhibitory effects. The manufacturer has received after starting amiodarone and may persist 1–3 reports of drug interactions with phenytoin that weeks after discontinuation. Most clinicians included nausea, vomiting, and vertigo.132 Due to recommend reducing the warfarin dosage by 25% phenytoin's narrow therapeutic window and when beginning amiodarone therapy.11, 142 nonlinear pharmacokinetics, these combinationsshould be avoided or phenytoin dosages reduced Significant Induction Interactions: S-Warfarin (Table 8).2, 11, 13, 15, 16, 19, 33, 65–68, 120, 132, 140–143 Patients previously stabilized with warfarin can Cases of mild phenytoin intoxication were suffer failed anticoagulation with the addition of rifampin, or overanticoagulation when rifampin cimetidine. Other H2 antagonists are without is discontinued.16, 114 Similar problems exist with these effects and would be more desirable coadministration of carbamazepine, phenobarbital, choices.13, 120 A study in eight healthy volunteers showed impaired elimination of phenytoin afteromeprazole 40 mg/day for 8 days. Phenytoin's Significant Inhibitory Interactions: Benzodiazepines elimination half-life was increased by an averageof 27%.65 Patients taking these combinations In vivo, omeprazole inhibits the metabolism of should be monitored closely, or lansoprazole may diazepam and increases the elimination half-life be given as an alternative in patients receiving of diazepam by an average of 130%. It is not entirely clear, but the interaction may be 2C9 An increase in phenytoin concentration seems mediated. Patients receiving this combination to be predictable when fluconazole is added.
over the long term should be monitored for side Nystagmus and ataxia occurred in two patients effects, or alternative agents should be considered.65 with excessive phenytoin concentrations afterinitiation of fluconazole 200–400 mg/day.140 Studies in healthy volunteers showed up to 75% Our knowledge of and ability to predict drug increase in AUC and 128% increase in trough phenytoin concentrations after 14 days of understanding of substrates, inhibitors, and inducers of CYP-450 isoenzymes. This review Isoniazid is another inhibitor that increases underscores the need for definitive in vivo drug phenytoin concentrations. This interaction seems interaction studies and continued patient to be most pronounced in slow acetylators.16 A reporting by clinicians, since in vitro data are not new antiepileptic agent, topiramate, also increases always consistent with in vivo experience and phenytoin serum concentrations up to 25% in since many variables (age, hepatic function, some patients. Patients should be monitored multiple metabolic pathways) influence patient carefully when receiving this combination outcomes. The information in this review should help health care providers in making decisions tomanage CYP-450 drug interactions. Clinicians Significant Induction Interactions: Phenytoin should be cognizant of potential interactions and Administration of rifampin with phenytoin and become familiar with the substrates, inhibitors, other anticonvulsants can cause therapeutic and inducers of the common enzymatic pathways failure due to enzyme induction. Serum concen- trations should be monitored regularly whenbeginning or discontinuing rifampin with these Acknowledgments
Special thanks to T. Donald Marsh, Pharm.D., FASHP, Director of Pharmacotherapy for the Mountain Significant Inhibitory Interactions: S-Warfarin Area Health Education Center and University of NorthCarolina Clinical Associate Professor of Pharmacy for The S-isomer of warfarin is metabolized by the editing and advising, and to the pharmacists at 2C9 isoenzyme. A significant interaction that Mission–St. Joseph’s Health System for their careful appears to be 2C9 mediated is with amiodarone and warfarin. Amiodarone decreases the totalbody clearance of both R- and S-warfarin. Any References
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