Drug Interactions in Dentistry

2004;135;298-311 J Am Dent Assoc

ELLIOT V. HERSH and PAUL A. MOORE importance of knowing your CYPs

Drug interactions in dentistry: The

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A B S T R A C T

298 JADA, Vol. 135, March 2004

C L I N I C A L P H A R M A C O L O G Y

Background. The hepatic and intestinalcytochrome, or CY, P450enzyme system is respon-sible for the biotransforma-tion of a multitude ofdrugs. Certain medicationsused in dentistry can actas substrates, inducers orinhibitors of this system. Methods. The authors conducted a MEDLINE search of articlesappearing between 1976 and the presentusing the keywords “drug interactions” and“cytochrome P450,” and reviewed reportsinvolving dental therapeutic agents usingPubMed links from an Indiana UniversityCYP450 drug interaction table on the WorldWide Web.Results. The antibiotics erythromycin andclarithromycin are potent inhibitors ofCYP3A4 and can increase blood levels andtoxicity of CYP3A4 substrates. Likewise,quinolone antibiotics such as ciprofloxacininhibit the metabolism of CYP1A2 sub-strates. Other dental therapeutic agents aresubstrates for CYP2C9 (celecoxib, ibuprofenand naproxen), CYP2D6 (codeine and tra-madol), CYP3A4 (methylprednisolone) andCYP2E1 (acetaminophen). Because codeineand tramadol are prodrugs, inhibition of theirmetabolism can lead to a diminution of theiranalgesic effects. While inducers ofacetaminophen metabolism, includingalcohol, theoretically can increase the propor-tion of it that is biotransformed into a poten-tially hepatotoxic metabolite, recent researchsuggests that concomitant alcohol intake doesnot increase the hepatotoxic potential of ther-apeutic doses of acetaminophen.Conclusions. A number of clinically sig-nificant drug interactions can arise withdental therapeutic agents that act as sub-strates or inhibitors of the CYP450 system.Clinical Implications. As polyphar-macy continues to increase, the likelihood ofadverse drug interactions in dentistry willincrease as well. Ensuring that patients’medical histories are up to date andacquiring knowledge of the various sub-strates, inducers and inhibitors of theCYP450 system will help practitionersavoid potentially serious adverse druginteractions.

Drug interactions in dentistryThe importance of knowingyour CYPs

ELLIOT V. HERSH, D.M.D., M.S., Ph.D.; PAUL A. MOORE, D.M.D., Ph.D., M.P.H.

As new drugs reach the marketplace andpatients take an increasing number andvariety of pharmaceutical agents for a host ofmedical conditions, the potential for seriousdrug interactions continues to grow.1 The

hepatic and intestinal cytochrome, or CY, P450 enzymesystem is responsible for the biotransformation of a mul-titude of drugs. As it is important for children to learn

their ABCs, it is becoming equallyimportant for dentists to learn theirCYPs, to lessen the chances of severedrug interactions’ appearing in theirpatients.

The CYP450 system is a group ofheme-containing enzymes embedded pri-marily in the lipid bilayer of the endo-plasmic recticulum of hepatocyteswithin the liver and enterocytes withinthe small intestine.2 CYP enzymes areinvolved in the oxidative metabolism ofa number of drug classes, as well as of avariety of endogenous substances,including prostaglandins and steroidhormones.

The current nomenclature of these enzymes is three-tiered: CYP followed by a number representing thefamily of enzymes, a letter representing the subfamilyand then another number representing the individualgene (for instance, CYP3A4).2,3 Each enzyme is termedan “isoform” or “isoenzyme.” More than 30 CYP450isoenzymes have been identified to date; the major onesresponsible for drug metabolism are CYP1A2, CYP2C9,CYP2C19, CYP2D6, CYP2E1 and CYP3A4. The humanCYP3A4 isoform is the most abundant cytochrome

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COVER STORY

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JADA, Vol. 135, March 2004 299


family expressed in the human liver and intes-tine, and thus is involved in the metabolism of agreater number of drugs and a greater proportionof adverse drug-drug interactions than are otherCYP isoforms.4

A substrate is a drug or endogenous compoundthat is metabolized by a particular CYP450 iso-form. Some substrates for the various CYP450isoforms are illustrated in Table 1.4,5 For example,the HIV protease inhibitors idinavir, nelfinivir,ritonavir and saquinavir—which, when combinedwith reverse transcriptase inhibitors, have

greatly improved the quality and longevity of lifein patients infected with the virus—are sub-strates for CYP3A4.5,6

Inducers of a specific CYP450 isoform (Table 2)increase the amount and subsequent activity ofthat particular enzyme in hepatic and smallintestinal tissue, potentially leading to dimin-ished plasma levels of active drugs that are sub-strates for that enzyme.2,3,5 In patients with HIVwho take protease inhibitors, the concomitantintake of the herbal antidepressant St. John’swort, which is available without a prescription,

TABLE 1

SOME SUBSTRATES FOR CYTOCHROME P450 ISOENZYMES.

CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP2E1

CYP3A4

Anesthetic agent, local: ropivacaineAnti-Alzheimer agent: tacrineAntiasthmatic agents: theophylline, zileutonAntidepressant agents: amitriptyline, clomipramine, fluvoxamine, imipramineAntipsychotic agents: clozapine, haloperidol

Angiotensin II receptor blockers: irbesartan, losartanAnticoagulant agent: warfarinAnticonvulsant agent: phenytoinCancer chemotherapeutic agent: tamoxifenHypoglycemic agents, oral: glipizide, glyburide, tolbutamideNSAIDs*: celecoxib, diclofenac, ibuprofen, naproxen

Antidepressant agents: amitriptyline, citalopram, clomipramine, imipramineBenzodiazepine: diazepamImmunosuppressant agent: cyclophosphamide (prodrug)Proton pump inhibitors: lansoprazole, omeprazole, pantopropazole

Analgesic agents, narcotic: codeine (prodrug), tramadol (prodrug)Anesthetic agent, local: lidocaineAntidepressant agents: amitriptyline, clomipramine, desipramine, imipramine, paroxetineAntipsychotic agents: haloperidol, perphenazine, risperidoneBeta blockers: carvedilol, metoprolol, propranolol, timolol

Analgesic agent, nonnarcotic: acetaminophenAnesthetic agents, general: enflurane, halothane, isoflurane, sevofluraneMuscle relaxant: chlorzoxazoneRecreational drug: ethanol

Analgesic agent, narcotic: alfentanilAnesthetic agent, local: lidocaineAntibiotic agents: clarithromycin, erythromycinAnticoagulant agent: warfarinAnticonvulsant agent: carbamazepineAntihistamine agents: astemizole,† terfenadine†Antipsychotic agents: haloperidol, pimozideBenzodiazepine agents: alprazolam, diazepam, midazolam, triazolamCalcium channel–blocking agents: amlodipine, diltiazem, felodipine,nifedipine, verapamilCholesterol-lowering drugs: atorvastatin, cerivastatin,† lovastatin (prodrug),simvastatin (prodrug)Corticosteroids: hydrocortisone, methylprednisolone HIV protease inhibitors: idinavir, nelfinivir, ritonavir, saquinavirHormonal agents: estradiol, progesteroneImmunosuppressant agents: cyclosporine, tacrolimusProkinetic agent: cisapride†

* NSAIDs: Nonsteroidal anti-inflammatory drugs.† No longer available in the United States.

ISOENZYME SUBSTRATE


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significantly decreases blood levels and theantiviral efficacy of these drugs because St.John’s wort is a potent inducer of CYP3A4.7

On the other hand, enzymeinhibitors (Table 3) reduce theactivity of a specific CYP450 iso-form, resulting in an accumulationof the substrate drug.2,3,5 The toxicitytypically encountered is identical towhat would be seen from an over-dose of the substrate drug. WithCYP3A4, it is not only drugs thatcan inhibit this isoform, but alsograpefruit juice, a seeminglyinnocuous food product.5,8-10 Itappears that bergamottin, a furan-coumarin, and possibly some other related com-pounds found in grapefruit juice both inhibit theaction of and reduce hepatic and intestinal con-centrations of CYP3A4,11,12 causing the accumula-tion of a number of CYP3A4 substrates. Theability of grapefruit to lead to excessive plasmaconcentrations of CYP3A4 substrates first wasdescribed for calcium channel antagonists, whereexcessive blood levels can lead to hypotension andperipheral edema.9,13 This was a serendipitousfinding (as so many scientific discoveries are);grapefruit juice was being used in the study only

to mask the taste ofethanol.9

The purpose of thisarticle is to introducereaders to some of themore clinically relevantadverse drug interac-tions involving theCYP450 system thatcould appear in dentalpractice. An excellentand continuallyupdated table ofCYP450 substrates,inducers and inhibitors,with links to key arti-cles and PubMed, canbe found on the WorldWide Web.5

METHODS

We conducted a searchon MEDLINE of arti-cles appearing between1976 and the present

employing the keywords “drug interactions” and“cytochrome P450” and reviewed reportsinvolving dental therapeutic agents. In addition,

we reviewed PubMed links forinteractions involving dental thera-peutic agents as found on theCytochrome P450 Drug InteractionTable posted on the World WideWeb by the Indiana UniversitySchool of Medicine’s Division ofClinical Pharmacology.5

RESULTS

A number of drugs used in dentalpractice can be involved in adversedrug-drug interactions as sub-

strates, inducers or inhibitors of the CYP450system. This article will discuss the clinical sig-nificance of these interactions.

Interactions involving CYP450 substrates.Benzodiazepines. Alprazolam, diazepam, mida-zolam and triazolam are substrates for CYP3A4,with diazepam being a substrate for CYP2C19 aswell. These drugs possess a wide therapeuticindex, and it is for this reason that they now arethe most widely used oral and injectable anxi-olytic agents in all of dental medicine.14 Whiledrug interactions with benzodiazepines theoreti-

TABLE 2

SOME INDUCERS OF CYTOCHROME P450 ISOENZYMES.

CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP2E1

CYP3A4

Antibiotic agent: rifampinAnticonvulsant agent: carbamazepineAntidiabetic agent: insulinFoods: chargrilled meatsRecreational drugs: tobacco

Antibiotic agent: rifampinBarbiturates: phenobarbital, secobarbital

Antibiotic agent: rifampinAnticonvulsant agent: carbamazepineHormonal agent: norethindrone

Antibiotic agent: rifampinCorticosteroid: dexamethasone

Antibiotic agent: isoniazidRecreational drugs: ethanol, tobacco

Antibiotic agents: rifabutin, rifampinAnticonvulsant agents: carbamazepine, phenytoinBarbiturates: phenobarbital, secobarbitalCorticosteroids: dexamethasone, hydrocortisone, prednisolone,methylprednisoloneHerbal remedy: St. John’s wortHIV antiviral agents: efavirenz, nevirapineOral hypoglycemic agents: pioglitazone, troglitazone

ISOENZYME INDUCER

Enzyme inhibitorsreduce the activity ofa specific cytochrome

P450 isoform,resulting in an

accumulation of thesubstrate drug.


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cally can involve inducers and inhibitors of thesespecific CYP450 isoforms, those involvinginhibitors of CYP3A4 are of most concern to theclinician. Like most interactions involving theCYP450 system, interactions involving benzodi-azepines are more likely to occur with the oraladministration of these drugs. These particulardrug interactions have been well-documented; theend result is benzodiazepine accumulation andprolonged and excessive sedation.15,16 Themacrolide antibiotics erythromycin and clar-ithromycin, which are used widely in dentistry,are potent inhibitors of CYP3A4. In one placebo-controlled study,17 erythromycin at 500 mil-ligrams three times per day for six days increasedpeak blood levels of a single dose of oral mida-zolam almost threefold (Figure 1). In addition,drowsiness and other indicators of psychomotorimpairment were far more intense in patientstaking erythromycin for six days than in thosetaking a placebo.17 Even a single dose of eryth-romycin taken concomitantly with oral mida-

zolam has been reported to increase the sedativeeffects of the benzodiazepine.18 By their ability toinhibit CYP3A4, azole antifungal drugs,4,19-21 pro-tease inhibitors (Figure 2),6,16,22 the selective sero-tonin reuptake blocker fluvoxamine and the serotonin-2 receptor antagonist nefezadone (bothantidepressants)23 and grapefruit juice24,25 all havebeen shown to significantly increase blood levels,elimination half-lives and the sedative andpsychomotor impairment effects of diazepam,alprazolam, midazolam and triazolam.

Narcotic analgesics. Codeine and tramadol aresubstrates for CYP2D6. They can be prescribedfor the control of postoperative pain as singleentities or in combination with aspirin (codeine)or acetaminophen (both codeine and tramadol). Inthe outpatient dental setting, combining mini-mally effective doses of these agents (60 mg ofcodeine or 75 mg of tramadol) with optimal ornear-optimal doses of aspirin or acetaminophen(600-1,000 mg) usually will provide better anal-gesia with fewer side effects than will simply

TABLE 3

SOME INHIBITORS OF CYTOCHROME P450 ISOENZYMES.

CYP1A2

CYP2C9

CYP2C19

CYP2D6

CYP2E1

CYP3A4

Antibiotic agents: ciprofloxacin, enoxacin, erythromycin, ofloxacinAntidepressant agent: fluvoxamineAntiplatelet agent: ticlopidineH2 receptor blocker: cimetidine

Antibiotic agents: isoniazid, metronidazole, sulfamethoxazole, trimethoprimAntidepressant agents: fluvoxamine, paroxetine, sertralineAntidysrhythmic agent: amiodaroneAntifungal agents: fluconazole, miconazole

Anticonvulsant agent: felbamateAntidepressant agents: fluoxetine, fluvoxamine, paroxetineAntifungal agent: ketoconazoleAntiplatelet agent: ticlopidineProton pump inhibitors: lansoprazole, omeprazole

Antidepressant agents: fluoxetine, paroxetine, sertralineAntidysrhythmic agents: amiodarone, quinidineH1 receptor blockers: chlorpheniramine, hydroxyzine, promethazineH2 receptor blockers: cimetidine, ranitidineNSAID*: celecoxibRecreational drug: cocaine

Alcoholism rehabilitation drug: disulfiram

Antibiotic agents: ciprofloxacin, clarithromycin, erythromycin, norfloxacinAntidepressant agents: fluvoxamine, nefazodoneAntidysrhythmic agent: amiodaroneAntifungal agents: fluconazole, itraconazole, ketoconazoleCalcium-channel blockers: diltiazem, verapamilFood product: grapefruit juiceH2 receptor blocker: cimetidineHIV protease inhibitors: idinavir, nelfinivir, ritonavir, saquinavir

* NSAID: Nonsteroidal anti-inflammatory drug.

ISOENZYME INHIBITOR


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administering a higher dose of the narcoticalone.26,27 Both agents are prodrugs; that is, theparent compound is essentially devoid of anal-gesic activity but the active demethylatedmetabolites—morphine in the case of codeine andO-demethyl tramadol in the case of tramadol—are responsible for the analgesic activity.28,29 TheCYP450 isoform responsible for this conversion isCYP2D6 (Figure 3). It has been demonstratedwith both drugs that the administration of theantidysrhythymic agent quinidine, a knownCYP2D6 inhibitor, essentially abolishes theiranalgesic activity.28,30 Other widely prescribedCYP2D6 inhibitors—including antidepressantagents of the selective serotonin reuptakeinhibitor class (fluoxetine, paroxetine and sertra-line) and the cyclo-oxygenase-, or COX-, 2–selective nonsteroidal anti-inflammatory drug, orNSAID, celecoxib—have the theoretical potentialto diminish the analgesic effects of both codeineand tramadol. The clinical significance of theseinteractions needs to be explored.

One other intriguing discovery with importantclinical implications is that CYP2D6 exhibits a

high degree of genetic polymorphism.28,30 From aclinical perspective, this means that there arepatients in the population who either poorly orextensively metabolize CYP2D6 substrates. Withprodrugs like codeine and tramadol, people whometabolize them poorly exhibit little analgesicactivity with the intake of these drugs becausethey do not form the necessary active metabolites,while people who metabolize them extensivelyreadily form the active metabolites and exhibitsignificant analgesia.28 Up to 10 percent of thewhite population are thought to metabolizeCYP2D6 substrates poorly.5 While this issue isoutside the scope of clinical practice, it is possiblethat in the future, a simple blood test for CYP2D6activity could be used to predict a patient’s likelyresponse to either agent.

Lidocaine. Lidocaine, the most frequently usedlocal anesthetic in all of dentistry, is a substratefor both CYP2D6 and CYP3A4.5 Because twoCYP450 isoforms control the drug’s metabolism,dramatic increases in lidocaine blood levels areunlikely to occur by the inhibition of a single isoform (for example, inhibition of CYP3A4 by

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Figure 1. Effects of placebo or erythromycin 500 mil-ligrams taken three times per day for six days on peakplasma levels (mean ± standard error) of a single oraldose of midazolam 15 mg. Blood levels of midazolamwere approximately threefold higher in the erythromycingroup (P = .003). Data adapted from Olkkola and col-leagues.17 ng/mL: Nanograms per milliliter.

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Figure 2. Effects of placebo or the protease inhibitorritonavir on the half-life of alprazolam. Alprazolam’shalf-life was 13 hours after taking placebo and 30 hoursafter taking ritonavir (P < .005). Data adapted fromGreenblatt and colleagues.22


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erythromycin). Four doses of erythromycin ethyl-succinate 600 mg given over two days modestlyincreased the half-life of an intravenous lidocaineinfusion from 2.2 to 2.8 hours.31 Of interest topediatric dentists, who frequently use antihis-tamines in sedative premedication regimens, theCYP2D6 inhibitors diphenhydramine and chlor-pheniramine impaired lidocaine metabolism inrodent hepatocytes.32 However, the ability of clas-sical antihistamines to increase blood levels of asingle dose of lidocaine after adental injection never has beendemonstrated in humans. In addi-tion, computer-simulated plasmaconcentration curves after theinjection of a single cartridge of 2percent lidocaine plus 1:100,000epinephrine revealed that even adoubling of lidocaine’s half-lifeincreased plasma concentrations byonly 9 percent.16 The most impor-tant ways to avoid local anesthetictoxicity in the outpatient dentalsetting are to use good aspiratingtechniques and to adhere strictly tomaximum recommended dosage guidelines.33,34

NSAIDs. The NSAIDs celecoxib, diclofenac,ibuprofen and naproxen are all substrates ofCYP2C9. As a group, NSAIDs are generally effi-cacious and well-tolerated for the short-termtreatment of postsurgical dental pain.35,36 As pre-viously described for the CYP2D6 substratescodeine and tramadol, there is a growing interestin genetic polymorphisms of CYP2C9.37-39 How-ever, because these NSAIDs are not prodrugs,people who metabolize them poorly would bemore prone to active drug accumulation and toxi-city (renal and gastrointestinal) with chronicdosing than would those who metabolize themextensively.37 Theoretically, drugs that areinhibitors of CYP2C9 (Table 3) also could impairthe metabolism and subsequent elimination ofthese four NSAIDs, leading to drug accumulation

and an increased likelihood of toxicity. However,it appears that other CYP450 isoforms also play arole in NSAID metabolism,38-40 so that inhibitorsof the single CYP2C9 isoform should not causedramatic increases in blood levels or half-lives ofthese NSAIDs, especially after short-term dosingfor acute pain.

Acetaminophen. Acetaminophen is the mostwidely sold over-the-counter, or OTC, analgesic-antipyretic agent in the United States.41 In addi-

tion to OTC sales, the number ofprescriptions dispensed in 2002 foracetaminophen-narcotic combina-tion drugs containing hydrocodone,codeine, propoxyphene and oxy-codone were ranked first, 32nd, 37thand 86th, respectively, of all pre-scribed medications in the UnitedStates.42 When used for the short-term treatment of pain or feveraccording to package insert guide-lines (maximum adult dose of 4grams per day), acetaminophenprobably is the safest of all the non-prescription analgesic agents.36,43

However, acute overdoses of acetaminophen—typically, 15 g or more in an adult—frequentlyresult in hepatotoxicity.36,44 In addition, multipleexcessive dose miscalculations administered tofebrile pediatric patients by their parents alsohave led to severe hepatotoxicity.45 In the case ofoverdose, an electrophilic toxic metabolite N-acetyl-p-benzoquinoneimine, or NAPQI, accumu-lates, resulting in hepatic cell death.44

When therapeutic doses of acetaminophen areconsumed, approximately 96 percent undergoesconjugation in the liver via the addition of a sul-fate or glucuronic acid group leading to the forma-tion of inactive-nontoxic metabolites (Figure 4).Via CYP2E1, the remaining 4 percent is con-verted to the highly reactive hepatotoxic metabo-lite NAPQI.44,46 However, this compound rapidlycombines with glutathione stores in the liver and

N-CH3 N-CH3

CH3O O OHOCodeine Morphine

CYP2D6

Tramadol O-Demethyl TramadolCH3O HO

OHOHCYP2D6

CH3 CH3

CH2

N

CH3 CH3

CH2

N

Figure 3. The demethylation of selected prodrugs to the active metabolites morphine and O-demethyl tramadol byCYP2D6. A. Codeine. B. Tramadol.

The ability of classicalantihistamines to

increase blood levelsof a single dose oflidocaine after adental injection never has beendemonstrated in

humans.

A B


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essentially is rendered harmless.46 In the case of amassive acetaminophen overdose, the excessiveproduction of NAPQI overwhelms the hepatic glu-tathione stores, resulting in alkylation of hepaticproteins and irreversible cellular damage unlessthe antidote N-acetylcysteine is administeredwithin the first 16 hours (before symptoms of theoverdose become clinically evident).36,44

Since CYP2E1 is an inducible enzyme, therehas been great concern over the possibility thatdrugs that are inducers of this enzyme, particu-larly ethanol, could promote the conversion ofacetaminophen to NAPQI, even in patients takingtherapeutic doses of the analgesic.46 An evengreater concern regarding acetaminophen hepato-toxicity has been voiced for patients with alco-holism. The thought is that not only couldCYP2E1 be induced in these patients, but alsoglutathione, which normally inactivates NAPQI,is known to be depleted in patients with alco-holism, further increasing the likelihood ofserious hepatotoxicity.36,46,47 Current U.S. Foodand Drug Administration-, or FDA-, approvedlabeling of OTC acetaminophen products reflectsthis concern; stating that “patients who consumethree or more alcoholic drinks per day should con-tact their physician before ingestingacetaminophen, because the combination mayincrease the risk of liver damage.”48 In addition,published recommendations limit the maximumdaily dose of acetaminophen to only 2 g inpatients with alcoholism to avoid additional liverdamage that is already present due to alcohol



abuse.47 Surprisingly, even with the restrictivelabeling and dosing of acetaminophen in combina-tion with alcohol, the interaction is not well-supported by scientific research.

As shown in Tables 1 and 2, ethanol can act asboth a substrate and an inducer of CYP2E1.5,44

Below blood levels of 250 milligrams per deciliter,ethanol preferentially occupies CYP2E1 overother substrates, resulting in the formation ofethanol metabolites while limiting its associa-tion with other substrates, including acetamino-phen.44,46,49 At concentrations greater than 250mg/dL, there also appears to be some de novo syn-thesis of CYP2E1, but experimental and com-puter models have revealed that even when maxi-mally induced, the production of NAPQI fromacetaminophen is increased only twofold.44 It hasbeen estimated that approximately 0.635 g ofNAPQI must be produced in a 150-pound adult toreach the threshold of liver toxicity. This is basedon the facts that approximately 4 percent of agiven acetaminophen dose is converted to NAPQIand an acute intake of 15.9 g of acetaminophen isneeded to reach the threshold of liver toxicity(0.04 × 15.9 g acetaminophen = 0.635 g NAPQI).44,50

If one extrapolates these calculations to a patientconsuming a full 1-g therapeutic dose ofacetaminophen, and having a high blood alcohollevel, the maximum concentration of NAPQIformed would only be 0.080 g (2 × 0.04 × 1 g), orapproximately eightfold less than needed to reachthe threshold of hepatotoxicity.

The simultaneous ingestion of alcohol has been shown to exert a hepatoprotective effect in patients taking massive overdoses ofacetaminophen.44,46,51 In one such case, a patientingested what usually is a lethal dose of 60 g ofacetaminophen after 48 hours of heavy drinkingof alcohol—and survived with little evidence ofhepatotoxicity.52 In this situation, alcohol prob-ably occupied a large proportion of the hepaticCYP2E1, limiting the association ofacetaminophen with the enzyme and the subse-quent production of NAPQI.36,46,49

With regard to patients with alcoholism takingtherapeutic doses of acetaminophen, a review ofmore than 2,000 reports revealed that Class I(controlled, randomized, blinded clinical trials)and Class II (prospective nonrandomized or non-blinded trials or well-designed case-controlstudies) data demonstrated little toxicity with thecombination.44,53 On the other hand, some ClassIII data relying exclusively on patient recall (ret-

Conjugated Metabolite N-acetyl-p-benzoquinoneimine(NAPQI)

Acetaminophen

Glutathione

CYP2E1 (4%)Glucuronidation

or Sulfation(96%)

NHCOCH3

NHCOCH3 NHCOCH3O

HO

RO

Figure 4. Metabolic fate of acetaminophen. The vastmajority of acetaminophen undergoes conjugation toinactive, nontoxic metabolites; “R” represents glucuronicacid or sulfate. Approximately 4 percent of the parentcompound is converted to the hepatotoxic metabolite N-acetyl-p-benzoquinoneimine which at therapeutic dosesof acetaminophen rapidly combines with glutathionestores in the liver and is inactivated.


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rospective case series, single case studies) sug-gested that “a morbid fate awaits some alcoholicpatients who ingest a therapeutic dose ofacetaminophen.”44 Thus, we are left with con-flicting results: well-designed reports suggestinglittle concern regarding using therapeutic doses ofacetaminophen in these patients, and purely ret-rospective cases suggesting a high likelihood oftoxicity. It appears that some patients with alco-holism who ingest massive overdoses ofacetaminophen (median dose of 54 g) may be atgreater risk of experiencing death than nonalco-holic patients who ingest similar amounts ofacetaminophen. The patient with chronic alco-holism may have decreased synthetic rates of aprotein transporter that moves glutathione fromthe hepatic cytosol into the mito-chondria. Since the mitochondriaare targeted by NAPQI, this mayexplain the increased toxicity of anacetaminophen overdose in thepatient with alcoholism.44 The FDAcontinues to hold hearings on theissue of alcohol and acetaminopheninteractions; it can be hoped thatfuture revisions to its acetamino-phen monograph (and, in fact, themonographs for all OTC analgesicagents with respect to alcohol con-sumption) will be based on evidenceand not solely on the results ofunsubstantiated case reports.54

Corticosteroids. Corticosteroidssuch as dexamethasone and methylprednisoloneare potent anti-inflammatory and immunosup-pressant agents. They frequently are used for ahost of chronic inflammatory and autoimmunediseases, including asthma, ulcerative colitis andlupus erythematosus and, in combination withother immunosuppressant agents, in the preven-tion of organ transplant rejection.55 In dentistry,therapeutic uses of glucocorticoids include thereduction of swelling after oral surgery proce-dures, the treatment of temporomandibular jointsyndrome symptoms (often by localized injection),the topical treatment of various oral-mucosallesions and as “stress steroids” in patients whosehypothalamic-pituitary-adrenal axis is sup-pressed.55 The actions of corticosteroids on theCYP450 system are complex, and various drugs ofthe class can act as both substrates and inducersof CYP3A4 isoform5,56 (Tables 1 and 2). Asinducers of CYP3A4, these agents could be pre-



dicted to be involved in numerous adverse druginteractions,57 in which their concomitant admin-istration would significantly reduce blood levels ofmany CYP3A4 substrates. However, this predic-tion has not been borne out in clinical studies.56,57

More important from a clinical perspective isthat because corticosteroids are substrates ofCYP3A4, their blood levels could become elevatedand their half-lives significantly increased whenan inhibitor of this enzyme is administered con-comitantly. This, in turn, would lead to anincreased potential for corticosteroid toxicity,including unwanted immunosuppression, sup-pression of the hypothalamic-pituitary-adrenalaxis and hyperglycemia. The corticosteroid thatseems most prone to these interactions is methyl-

prednisolone,58-64 an agent fre-quently administered in a six-day,21-dose regimen (a dose-pack) toreduce postoperative swelling afterdental impaction surgery.CYP3A4-inhibitor drugs that havebeen documented to cause theaccumulation of methylpred-nisolone include the macrolideantibiotic drugs erythromycin andclarithromycin,58,59 the azole anti-fungal drugs itraconazole and keto-conazole,60,61 the calcium-channel–blocking agents diltiazemand mibefradil62,63 and 200 mL ofdouble-strength grapefruit juice.64

It is likely that other CYP3A4inhibitors also could interact adversely withmethylprednisolone. Clinicians should be awareof these potential interactions and advise patientsto avoid the ingestion of grapefruit juice duringtheir course of methylprednisolone therapy andfor at least three days afterward.

Interactions involving CYP450 inducers.Barbiturates. Derivatives of barbituric acid,including phenobarbital and secobarbital, oncewere important drugs in oral sedation techniquesused with anxious dental patients. However,because of their low therapeutic index, high abusepotential, disruptions of rapid-eye-movement–stage sleep and the potential for numerous druginteractions, they have been replaced largely bybenzodiazepines.14,65 Barbiturates are known toinduce various isoforms of the CYP450 systems,including CYP2C9 and CYP3A4, leading to adecrease in blood levels of a number of drugs.This has been documented for the antidys-

Some patients withalcoholism who ingestmassive overdoses ofacetaminophen maybe at greater risk ofexperiencing deaththan nonalcoholic

patients who ingestsimilar amounts of

acetaminophen.


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rhythmic agent quinidine, azole antifungalagents, nifedipine and other calcium-channelblockers, the cancer chemotherapeutic agentetoposide, oral contraceptive agents containingestradiol and progesterone, the immunosuppres-sant agents cyclosporine and tacrolimus, variousHIV protease inhibitors, methadone and war-farin, among others.2,3,66 Acute (single-dose) barbi-turate therapy that typically was used in dentalsedative techniques probably was only rarelyinvolved in adverse drug interactions involvingthe induction of the CYP450 system, becauseinduction typically takes at least several days ofbarbiturate use.2 Longer-term therapy, such assometimes used for temporomandibular joint dys-function and headache,67 indeedcould cause blood levels of thesedrugs to fall below therapeuticlevels. For example, a patienttaking cyclosporine or tacrolimusbecause of an organ transplant the-oretically could experience acuterejection of that organ. Likewise, apatient taking oral contraceptivescould begin ovulating and becomepregnant while receiving barbitu-rate therapy. To avoid drug inter-actions of this type, clinicians also are cautionedto recognize brand-name drugs with “hidden” bar-biturate components such as the popularmigraine drug Fiorinal (Novartis Pharmaceuti-cals, East Hanover, N.J.), which contains 325 mgof aspirin plus 50 mg of the barbiturate butal-bital.

Interactions involving CYP450 inhibitors.Interestingly, the agents used in dental practicethat can act as inhibitors of various CYP450 iso-forms all are antimicrobial agents. Antimicrobialagents are dosed on a more chronic basis than areother therapeutic agents (such as local anesthetic,analgesic and anxiolytic agents) routinely used indentistry, which enhances the likelihood of clini-cally significant CYP450 inhibition and the asso-ciated drug interactions with CYP450 sub-strates.15 These interactions as a whole can beextremely serious and potentially life-threateningif the substrate drug whose metabolism is beinginhibited has a low margin of safety or whatpharmacologists call a “low therapeutic index.”1,15

Quinolone antibiotic agents. Members of thequinolone class include ciprofloxacin, enoxacin,norfloxacin and ofloxacin. Of these agents, theuse of systemic ciprofloxacin (typically at a dose of



500 mg twice per day for 10 days) is becomingincreasingly popular in the treatment of refrac-tory periodontal infections that harbor Acti-nobacillus actinomycetemcomitans and othergram-negative, facultatively anaerobic rods.68-70

Ciprofloxacin is a potent inhibitor of CYP1A2 andalso produces some inhibition of CYP3A4. Themost clinically significant interaction involvingciprofloxacin is its ability to inhibit themetabolism of the CYP1A2 substrate theo-phylline.71,72 While increases in theophylline bloodconcentrations and half-life average only about 20to 30 percent, the drug has a rather low thera-peutic index. Cardiac dysrhythmias and convul-sions are the most serious consequence of exces-

sive blood levels of theophylline.It has been reported that a reg-

imen of ciprofloxacin 250 mg takentwice per day for seven daysincreased average plasma concen-trations of the atypical antipsy-chotic agent clozapine (a CYP1A2substrate) by approximately 30 per-cent.73 In one patient, a regimen ofciprofloxacin 500 mg twice per dayincreased plasma concentrations ofclozapine by 80 percent.74 Elevated

plasma clozapine levels increase the risk ofoversedation, urinary retention, constipation andseizures in a patient population in which noncom-pliance with schizophrenic medication regimensalready is the norm because of the nature of thedisease and the unwanted side effects associatedwith this class of drugs.75

Metronidazole. Metronidazole is highly effec-tive against obligate anaerobic bacteria associ-ated with periodontal disease, periapicalabscesses and peri-implantitis.76-79 Because it hasno activity against facultative anaerobic bacteria,which can be part of a mixed flora inhabitingthese infected sites, metronidazole frequently is combined with a penicillin or with ciproflox-acin.76-78 With respect to drug interactions,metronidazole is best known for its interactionwith alcohol. This combination can result in adisulfiram-like reaction, which tends to be morefrightening than serious, with patients experi-encing nausea, vomiting, headache and cardiacpalpitations.15 These symptoms are best explainedby metronidazole’s ability to block a key enzymein alcohol metabolism, namely acetaldehydedehydrogenase, causing acetaldehyde to accumu-late in the bloodstream after alcohol consumption.

Clinicians are cautioned to

recognize brand-name drugs

with ‘hidden’ barbiturate

components.


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This adverse drug interaction, however, appearsto be unrelated to the inhibition of CYP450enzymes.

Metronidazole also may be involved in otherdrug interactions that relate to its ability toinhibit CYP2C9 (Table 3). While a number of sub-strates are metabolized by this isoenzyme, theinteraction that appears best documented is theability of metronidazole to significantly increasethe blood concentrations, half-life and the associ-ated hemorrhagic potential of the anticoagulantagent warfarin.80,81 In addition, metronidazole’sability to cause the accumulation of theantiepileptic drug and CYP2C9 substrate pheny-toin is supported by at least one well-designedclinical trial.82 Excessive phenytoin levels in theblood increase the risk of drowsi-ness, confusion, diplopia, ataxiaand nystagmus.83 Before pre-scribing metronidazole to a dentalpatient who is receiving chronicwarfarin or phenytoin therapy, den-tists are advised to consult with thepatient’s prescribing physician.

Macrolide antibiotic agents. His-torically, erythromycin was consid-ered to be the antibiotic agent ofchoice for patients with penicillinallergies who had odontogenicinfections.84 However, because of ahigh incidence of gastrointestinal complaints,increasing bacterial resistance problems and onlymoderate activity against anerobic bacteria, itsuse has been decreasing. Clarithromycin isbetter-tolerated than erythromycin; possessesbetter activity against most streptococcal, staphy-lococcal and anaerobic bacterial species; and,while more expensive than erythromycin, mayresult in better patient compliance because it hasto be taken only twice per day.78,84 Like clar-ithromycin, azithromycin has excellent activityagainst anaerobes, possesses an extended half-life(requiring only once-per-day dosing) and is analternative to amoxicillin in patients requiringendocarditis-related prophylaxis who are allergicto penicillins.85 For this indication, both drugs aredosed at 500 mg one hour before the dental procedure.

Erythromycin and clarithromycin are potentinhibitors of CYP3A4 and are associated withnumerous untoward drug interactions,2,3,5,8,15 whileazithromycin is not.5,86-88 This difference betweenthe macrolides probably is structurally related.



Erythromycin and clarithromycin possess 14carbon atoms surrounding their macrocyclic lac-tone rings, while azithromycin contains 15 ofthese constituents.89 The primary reason for thevast number of potential drug interactions withCYP3A4 inhibitors is the fact that CYP3A4 hasbroad substrate specificity and has been esti-mated to contribute to the metabolism of morethan 50 percent of all available therapeuticagents.57 Since the pharmacokinetic consequencesof all these interactions is an accumulation of thesubstrate drug, side effects of the substrate drug,including relatively rare side effects, become morecommon and more intense. Typically, the morechronic the dosing with the substrate and theinhibitor, the greater the chance for a clinically

significant drug interaction. How-ever, if the substrate undergoes sig-nificant (greater than 60 percent)CYP3A4 metabolism in the gut andthe liver before reaching the sys-temic circulation, the likelihood of asignificant drug interactionincreases, even with just one or twodoses of the substrate drug.8 Exam-ples of CYP3A4 substrates with rel-atively low oral bioavailabilityinclude terfenadine, astemizole,simvastatin, lovastatin, felodipineand midazolam.

The ability of erythromycin and clarithromycinto inhibit the CYP3A4-directed metabolism of cer-tain benzodiazepines15-18 and methylpredniso-lone58,59 already has been discussed. Table 4 sum-marizes some additional interactions betweenCYP3A4 substrates and antimicrobial CYP3A4inhibitors used in dentistry.86,90-138 Some of thesesubstrates—including the nonsedating antihis-tamine agents terfenadine and astemizole, theprokinetic agent (gastroesophageal reflux drug)cisapride and the lipid-lowering drug ceriva-statin—have been removed from the U.S. marketby the FDA, partly because of an unacceptablyhigh incidence of usually rare life-threateningtoxicities (torsades de pointes with terfenadine,astemizole and cisapride and rhabdomyolysiswith cerivastatin) when administered concomi-tantly with CYP3A4 inhibitors.

Azole antifungal drugs. This group of anti-fungal agents blocks the fungal CYP450-directedsynthesis of the cell membrane component ergos-terol in sensitive organisms.139 Unfortunately, thismechanism of action leads to inhibition of human

Metronidazole cansignificantly increase

the blood concentrations,

half-life and the associated

hemorrhagic potentialof the anticoagulant

agent warfarin.


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CYP450 isoforms, especially CYP3A4. Of thisgroup, ketoconazole and itraconazole are associ-ated with by far the greatest incidence of adversedrug interactions, resulting in the accumulationand subsequent toxicity of a number of CYP3A4

substrates (Table 4). Fortunately, these drugs arerarely, if ever, used in outpatient dentistry. How-ever, caution still is advised when administeringfluconazole or clotrimazole to treat oral candidi-asis in patients taking CYP3A4 substrates.

TABLE 4

SOME ADVERSE DRUG:DRUG INTERACTIONS INVOLVING ERYTHROMYCIN, CLARITHROMYCIN, KETOCONAZOLE AND ITRACONAZOLE WITH CYP3A4 SUBSTRATES.

Astemizole, Cisapride,Pimozide, Terfenadine

Atorvastatin,Cerivastatin, Lovastatin, Simvastatin

Felodipine,Nifedipine

Cyclosporine,Tacrolimus

Warfarin

Carbamazepine

Theophylline

Substrate accumulation leading tocardiac QT interval prolongationand torsades de pointes ventric-ular tachycardia86, 90-100

Substrate accumulation leading todiffuse myalgias, rhabdomyolysisand renal failure101-106

Substrate accumulation leading to severe hypotension and edema109-111

Substrate accumulation leading toenhanced immunosuppression andnephrotoxicity112-116

Substrate accumulation leading toincreased prothrombin times,international normalized ratiosand increased risk of seriousbleeding119-123

Substrate accumulation leading toincreased risk of ataxia, vertigo,drowsiness and confusion125-130

Substrate accumulation leading toincreased risk of tremors, cardiacdysrhythmias and seizures133-138

Torsades de pointes is a life-threateningventricular dysrhythmia that occurs in thesetting of electrocardiographic QT intervalprolongation. While terfenadine, astemi-zole and cisapride no longer are availablein the United States, pimozide still is usedin the treatment of psychotic disorders andis especially effective in the managementof Gilles de la Tourette’s syndrome.100

The “statin” drugs inhibit the rate-limitingstep (3-hydroxy-3-methyl-glutaryl coen-zyme A, or HMG-CoA, reductase) incholesterol biosynthesis and are usedwidely for this purpose.42 Rhabdomyolysisis a potentially life-threatening breakdownof skeletal muscle, resulting in the releaseof myoglobin into the serum and urine andgiving the urine a brown-rust color. Themyoglobin can cause blockage of the renaltubular system, resulting in kidneydamage and acute renal failure.107

Recently, a single case of a possible fluconazole-simvastatin interaction wasreported.108

This interaction is an extension of theantihypertensive effects of the substrates.Other calcium-channel blockers also maybe predisposed to the interaction.

This interaction has been used therapeuti-cally to reduce the cost of immunosuppres-sant therapy.117 Clotrimazole, in the formof troches—frequently used in the treat-ment of oral candidiasis—also significantlyincreases tacrolimus blood levels.118

Fluconazole also increases warfarin bloodlevels via an inhibition of warfarin’sCYP2C9 metabolism.124

Two cases of a possible fluconazole-carbamazepine interaction have beenreported.131,132

This interaction appears to involve onlyerythromycin, possibly owing to its abilityto inhibit CYP1A2, of which theophyllineis a substrate.2,138

* The use of alternative antibiotics (penicillin, tetracycline, azithromycin or clindamycin) or antifungals (topical nystatin or amphotericin B) that are appropriate for the specific infection is advised when patients are taking these CYP3A4 substrates.

CYP3A4 SUBSTRATES POTENTIAL INTERACTION COMMENTS*


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Potentially serious interactions have beenreported when these agents are administered topatients taking simvastatin, tacrolimus, warfarinor carbamazepine.108,118,124,131,132

CONCLUSIONS

The CYP450 system is responsible for themetabolism of a multitude of diverse pharmaco-logical agents. Drugs routinely used in dentistryoften serve as substrates or inhibitors of thissystem. Dentists can avoid untoward drug inter-actions in their practices by gaining an under-standing of the CYP450 substrates, inducers andinhibitors. ■

Dr. Hersh is a professor of oral surgery and pharmacology and asso-ciate dean of clinical research, University of Pennsylvania School ofDental Medicine, Philadelphia, Pa. 19104-6030, e-mail “[email protected]”. Address reprint requests to Dr. Hersh.

Dr. Moore is a professor of pharmacology and dental public health,University of Pittsburgh School of Dental Medicine, Pittsburgh.

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