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J Am Dent Assoc, Vol 135, No 3, 298-311.
© 2004 American Dental Association
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CLINICAL PHARMACOLOGY

COVER STORY
JADA Continuing Education

Drug interactions in dentistry

The importance of knowing your CYPs



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


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 CONCLUSIONS
 REFERENCES
 
Background. The hepatic and intestinal cytochrome, or CY, P450 enzyme system is responsible for the biotransformation of a multitude of drugs. Certain medications used in dentistry can act as substrates, inducers or inhibitors of this system.

Methods. The authors conducted a MEDLINE search of articles appearing between 1976 and the present using the keywords "drug interactions" and "cytochrome P450," and reviewed reports involving dental therapeutic agents using PubMed links from an Indiana University CYP450 drug interaction table on the World Wide Web.

Results. The antibiotics erythromycin and clarithromycin are potent inhibitors of CYP3A4 and can increase blood levels and toxicity of CYP3A4 substrates. Likewise, quinolone antibiotics such as ciprofloxacin inhibit the metabolism of CYP1A2 substrates. Other dental therapeutic agents are substrates for CYP2C9 (celecoxib, ibuprofen and naproxen), CYP2D6 (codeine and tramadol), CYP3A4 (methylprednisolone) and CYP2E1 (acetaminophen). Because codeine and tramadol are prodrugs, inhibition of their metabolism can lead to a diminution of their analgesic effects. While inducers of acetaminophen metabolism, including alcohol, theoretically can increase the proportion of it that is biotransformed into a potentially hepatotoxic metabolite, recent research suggests that concomitant alcohol intake does not increase the hepatotoxic potential of therapeutic doses of acetaminophen.

Conclusions. A number of clinically significant drug interactions can arise with dental therapeutic agents that act as substrates or inhibitors of the CYP450 system.

Clinical Implications. As polypharmacy continues to increase, the likelihood of adverse drug interactions in dentistry will increase as well. Ensuring that patients’ medical histories are up to date and acquiring knowledge of the various substrates, inducers and inhibitors of the CYP450 system will help practitioners avoid potentially serious adverse drug interactions.

As new drugs reach the marketplace and patients take an increasing number and variety of pharmaceutical agents for a host of medical conditions, the potential for serious drug interactions continues to grow.1 The hepatic and intestinal cytochrome, or CY, P450 enzyme system is responsible for the biotransformation of a multitude of drugs. As it is important for children to learn their ABCs, it is becoming equally important for dentists to learn their CYPs, to lessen the chances of severe drug interactions’ appearing in their patients.

Acquiring knowledge of the cytochrome P450 system will help practitioners avoid potentially serious adverse drug interactions.

The CYP450 system is a group of heme-containing enzymes embedded primarily in the lipid bilayer of the endoplasmic recticulum of hepatocytes within the liver and enterocytes within the small intestine.2 CYP enzymes are involved in the oxidative metabolism of a number of drug classes, as well as of a variety of endogenous substances, including prostaglandins and steroid hormones.

The current nomenclature of these enzymes is three-tiered: CYP followed by a number representing the family of enzymes, a letter representing the subfamily and then another number representing the individual gene (for instance, CYP3A4).2,3 Each enzyme is termed an "isoform" or "isoenzyme." More than 30 CYP450 isoenzymes have been identified to date; the major ones responsible for drug metabolism are CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4. The human CYP3A4 isoform is the most abundant cytochrome family expressed in the human liver and intestine, and thus is involved in the metabolism of a greater number of drugs and a greater proportion of adverse drug-drug interactions than are other CYP isoforms.4

A substrate is a drug or endogenous compound that is metabolized by a particular CYP450 isoform. Some substrates for the various CYP450 isoforms are illustrated in Table 1Go.4,5 For example, the HIV protease inhibitors idinavir, nelfinivir, ritonavir and saquinavir—which, when combined with reverse transcriptase inhibitors, have greatly improved the quality and longevity of life in patients infected with the virus—are substrates for CYP3A4.5,6


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  		TABLE 1 SOME SUBSTRATES FOR CYTOCHROME P450 ISOENZYMES.

 
Inducers of a specific CYP450 isoform (Table 2Go) increase the amount and subsequent activity of that particular enzyme in hepatic and small intestinal tissue, potentially leading to diminished plasma levels of active drugs that are substrates for that enzyme.2,3,5 In patients with HIV who take protease inhibitors, the concomitant intake of the herbal antidepressant St. John’s wort, which is available without a prescription, significantly decreases blood levels and the antiviral efficacy of these drugs because St. John’s wort is a potent inducer of CYP3A4.7


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  		TABLE 2 SOME INDUCERS OF CYTOCHROME P450 ISOENZYMES.

 
Enzyme inhibitors reduce the activity of a specific cytochrome P450 isoform, resulting in an accumulation of the substrate drug.

On the other hand, enzyme inhibitors (Table 3Go) reduce the activity of a specific CYP450 isoform, resulting in an accumulation of the substrate drug.2,3,5 The toxicity typically encountered is identical to what would be seen from an overdose of the substrate drug. With CYP3A4, it is not only drugs that can inhibit this isoform, but also grapefruit juice, a seemingly innocuous food product.5,8–10 It appears that bergamottin, a furan-coumarin, and possibly some other related compounds found in grapefruit juice both inhibit the action of and reduce hepatic and intestinal concentrations of CYP3A4,11,12 causing the accumulation of a number of CYP3A4 substrates. The ability of grapefruit to lead to excessive plasma concentrations of CYP3A4 substrates first was described for calcium channel antagonists, where excessive blood levels can lead to hypotension and peripheral edema.9,13 This was a serendipitous finding (as so many scientific discoveries are); grapefruit juice was being used in the study only to mask the taste of ethanol.9


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  		TABLE 3 SOME INHIBITORS OF CYTOCHROME P450 ISOENZYMES.

 
The purpose of this article is to introduce readers to some of the more clinically relevant adverse drug interactions involving the CYP450 system that could appear in dental practice. An excellent and continually updated table of CYP450 substrates, inducers and inhibitors, with links to key articles and PubMed, can be found on the World Wide Web.5


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 CONCLUSIONS
 REFERENCES
 
We conducted a search on MEDLINE of articles appearing between 1976 and the present employing the keywords "drug interactions" and "cytochrome P450" and reviewed reports involving dental therapeutic agents. In addition, we reviewed PubMed links for interactions involving dental therapeutic agents as found on the Cytochrome P450 Drug Interaction Table posted on the World Wide Web by the Indiana University School of Medicine’s Division of Clinical Pharmacology.5


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
CONCLUSIONS
 REFERENCES
 
A number of drugs used in dental practice can be involved in adverse drug-drug interactions as substrates, inducers or inhibitors of the CYP450 system. This article will discuss the clinical significance of these interactions.

Interactions involving CYP450 substrates. Benzodiazepines. Alprazolam, diazepam, midazolam and triazolam are substrates for CYP3A4, with diazepam being a substrate for CYP2C19 as well. These drugs possess a wide therapeutic index, and it is for this reason that they now are the most widely used oral and injectable anxiolytic agents in all of dental medicine.14 While drug interactions with benzodiazepines theoretically can involve inducers and inhibitors of these specific CYP450 isoforms, those involving inhibitors of CYP3A4 are of most concern to the clinician. Like most interactions involving the CYP450 system, interactions involving benzodiazepines are more likely to occur with the oral administration of these drugs. These particular drug interactions have been well-documented; the end result is benzodiazepine accumulation and prolonged and excessive sedation.15,16 The macrolide antibiotics erythromycin and clarithromycin, which are used widely in dentistry, are potent inhibitors of CYP3A4. In one placebo-controlled study,17 erythromycin at 500 milligrams three times per day for six days increased peak blood levels of a single dose of oral midazolam almost threefold (Figure 1Go). In addition, drowsiness and other indicators of psychomotor impairment were far more intense in patients taking erythromycin for six days than in those taking a placebo.17 Even a single dose of erythromycin taken concomitantly with oral midazolam has been reported to increase the sedative effects of the benzodiazepine.18 By their ability to inhibit CYP3A4, azole antifungal drugs,4,19–21 protease inhibitors (Figure 2Go),6,16,22 the selective serotonin reuptake blocker fluvoxamine and the serotonin-2 receptor antagonist nefezadone (both antidepressants)23 and grapefruit juice24,25 all have been shown to significantly increase blood levels, elimination half-lives and the sedative and psychomotor impairment effects of diazepam, alprazolam, midazolam and triazolam.



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  		Figure 1. Effects of placebo or erythromycin 500 milligrams taken three times per day for six days on peak plasma levels (mean ± standard error) of a single oral dose of midazolam 15 mg. Blood levels of midazolam were approximately threefold higher in the erythromycin group (P = .003). Data adapted from Olkkola and colleagues.17 ng/mL: Nanograms per milliliter.

 


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

 
Narcotic analgesics. Codeine and tramadol are substrates for CYP2D6. They can be prescribed for the control of postoperative pain as single entities or in combination with aspirin (codeine) or acetaminophen (both codeine and tramadol). In the outpatient dental setting, combining minimally effective doses of these agents (60 mg of codeine or 75 mg of tramadol) with optimal or near-optimal doses of aspirin or acetaminophen (600–1,000 mg) usually will provide better analgesia with fewer side effects than will simply administering a higher dose of the narcotic alone.26,27 Both agents are prodrugs; that is, the parent compound is essentially devoid of analgesic activity but the active demethylated metabolites—morphine in the case of codeine and O-demethyl tramadol in the case of tramadol—are responsible for the analgesic activity.28,29 The CYP450 isoform responsible for this conversion is CYP2D6 (Figure 3Go). It has been demonstrated with both drugs that the administration of the antidysrhythymic agent quinidine, a known CYP2D6 inhibitor, essentially abolishes their analgesic activity.28,30 Other widely prescribed CYP2D6 inhibitors—including antidepressant agents of the selective serotonin reuptake inhibitor class (fluoxetine, paroxetine and sertraline) and the cyclo-oxygenase-, or COX-, 2–selective nonsteroidal anti-inflammatory drug, or NSAID, celecoxib—have the theoretical potential to diminish the analgesic effects of both codeine and tramadol. The clinical significance of these interactions needs to be explored.



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  		Figure 3. The demethylation of selected prodrugs to the active metabolites morphine and O-demethyl tramadol by CYP2D6. A. Codeine. B. Tramadol.

 
One other intriguing discovery with important clinical implications is that CYP2D6 exhibits a high degree of genetic polymorphism.28,30 From a clinical perspective, this means that there are patients in the population who either poorly or extensively metabolize CYP2D6 substrates. With prodrugs like codeine and tramadol, people who metabolize them poorly exhibit little analgesic activity with the intake of these drugs because they do not form the necessary active metabolites, while people who metabolize them extensively readily form the active metabolites and exhibit significant analgesia.28 Up to 10 percent of the white population are thought to metabolize CYP2D6 substrates poorly.5 While this issue is outside the scope of clinical practice, it is possible that in the future, a simple blood test for CYP2D6 activity could be used to predict a patient’s likely response to either agent.

Lidocaine. Lidocaine, the most frequently used local anesthetic in all of dentistry, is a substrate for both CYP2D6 and CYP3A4.5 Because two CYP450 isoforms control the drug’s metabolism, dramatic increases in lidocaine blood levels are unlikely to occur by the inhibition of a single isoform (for example, inhibition of CYP3A4 by erythromycin). Four doses of erythromycin ethylsuccinate 600 mg given over two days modestly increased the half-life of an intravenous lidocaine infusion from 2.2 to 2.8 hours.31 Of interest to pediatric dentists, who frequently use antihistamines in sedative premedication regimens, the CYP2D6 inhibitors diphenhydramine and chlorpheniramine impaired lidocaine metabolism in rodent hepatocytes.32 However, the ability of classical antihistamines to increase blood levels of a single dose of lidocaine after a dental injection never has been demonstrated in humans. In addition, computer-simulated plasma concentration curves after the injection of a single cartridge of 2 percent lidocaine plus 1:100,000 epinephrine revealed that even a doubling of lidocaine’s half-life increased plasma concentrations by only 9 percent.16 The most important ways to avoid local anesthetic toxicity in the outpatient dental setting are to use good aspirating techniques and to adhere strictly to maximum recommended dosage guidelines.33,34

The ability of classical antihistamines to increase blood levels of a single dose of lidocaine after a dental injection never has been demonstrated in humans.

NSAIDs. The NSAIDs celecoxib, diclofenac, ibuprofen and naproxen are all substrates of CYP2C9. As a group, NSAIDs are generally efficacious and well-tolerated for the short-term treatment of postsurgical dental pain.35,36 As previously described for the CYP2D6 substrates codeine and tramadol, there is a growing interest in genetic polymorphisms of CYP2C9.37–39 However, because these NSAIDs are not prodrugs, people who metabolize them poorly would be more prone to active drug accumulation and toxicity (renal and gastrointestinal) with chronic dosing than would those who metabolize them extensively.37 Theoretically, drugs that are inhibitors of CYP2C9 (Table 3Go) also could impair the metabolism and subsequent elimination of these four NSAIDs, leading to drug accumulation and an increased likelihood of toxicity. However, it appears that other CYP450 isoforms also play a role in NSAID metabolism,38–40 so that inhibitors of the single CYP2C9 isoform should not cause dramatic increases in blood levels or half-lives of these NSAIDs, especially after short-term dosing for acute pain.

Acetaminophen. Acetaminophen is the most widely sold over-the-counter, or OTC, analgesic-antipyretic agent in the United States.41 In addition to OTC sales, the number of prescriptions dispensed in 2002 for acetaminophen-narcotic combination drugs containing hydrocodone, codeine, propoxyphene and oxycodone were ranked first, 32nd, 37th and 86th, respectively, of all prescribed medications in the United States.42 When used for the short-term treatment of pain or fever according to package insert guidelines (maximum adult dose of 4 grams per day), acetaminophen probably 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—frequently result in hepatotoxicity.36,44 In addition, multiple excessive dose miscalculations administered to febrile pediatric patients by their parents also have led to severe hepatotoxicity.45 In the case of overdose, an electrophilic toxic metabolite N-acetyl-p-benzoquinoneimine, or NAPQI, accumulates, resulting in hepatic cell death.44

When therapeutic doses of acetaminophen are consumed, approximately 96 percent undergoes conjugation in the liver via the addition of a sulfate or glucuronic acid group leading to the formation of inactive-nontoxic metabolites (Figure 4Go). Via CYP2E1, the remaining 4 percent is converted to the highly reactive hepatotoxic metabolite NAPQI.44,46 However, this compound rapidly combines with glutathione stores in the liver and essentially is rendered harmless.46 In the case of a massive acetaminophen overdose, the excessive production of NAPQI overwhelms the hepatic glutathione stores, resulting in alkylation of hepatic proteins and irreversible cellular damage unless the antidote N-acetylcysteine is administered within the first 16 hours (before symptoms of the overdose become clinically evident).36,44



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  		Figure 4. Metabolic fate of acetaminophen. The vast majority of acetaminophen undergoes conjugation to inactive, nontoxic metabolites; "R" represents glucuronic acid or sulfate. Approximately 4 percent of the parent compound is converted to the hepatotoxic metabolite N-acetyl-p-benzoquinoneimine which at therapeutic doses of acetaminophen rapidly combines with glutathione stores in the liver and is inactivated.

 
Since CYP2E1 is an inducible enzyme, there has been great concern over the possibility that drugs that are inducers of this enzyme, particularly ethanol, could promote the conversion of acetaminophen to NAPQI, even in patients taking therapeutic doses of the analgesic.46 An even greater concern regarding acetaminophen hepatotoxicity has been voiced for patients with alcoholism. The thought is that not only could CYP2E1 be induced in these patients, but also glutathione, which normally inactivates NAPQI, is known to be depleted in patients with alcoholism, further increasing the likelihood of serious hepatotoxicity.36,46,47 Current U.S. Food and Drug Administration-, or FDA-, approved labeling of OTC acetaminophen products reflects this concern; stating that "patients who consume three or more alcoholic drinks per day should contact their physician before ingesting acetaminophen, because the combination may increase the risk of liver damage."48 In addition, published recommendations limit the maximum daily dose of acetaminophen to only 2 g in patients with alcoholism to avoid additional liver damage that is already present due to alcohol abuse.47 Surprisingly, even with the restrictive labeling and dosing of acetaminophen in combination with alcohol, the interaction is not well-supported by scientific research.

As shown in Tables 1Go and 2Go, ethanol can act as both a substrate and an inducer of CYP2E1.5,44 Below blood levels of 250 milligrams per deciliter, ethanol preferentially occupies CYP2E1 over other substrates, resulting in the formation of ethanol metabolites while limiting its association with other substrates, including acetaminophen.44,46,49 At concentrations greater than 250 mg/dL, there also appears to be some de novo synthesis of CYP2E1, but experimental and computer models have revealed that even when maximally induced, the production of NAPQI from acetaminophen is increased only twofold.44 It has been estimated that approximately 0.635 g of NAPQI must be produced in a 150-pound adult to reach the threshold of liver toxicity. This is based on the facts that approximately 4 percent of a given acetaminophen dose is converted to NAPQI and an acute intake of 15.9 g of acetaminophen is needed to reach the threshold of liver toxicity (0.04 x 15.9 g acetaminophen = 0.635 g NAPQI).44,50 If one extrapolates these calculations to a patient consuming a full 1-g therapeutic dose of acetaminophen, and having a high blood alcohol level, the maximum concentration of NAPQI formed would only be 0.080 g (2 x 0.04 x 1 g), or approximately eightfold less than needed to reach the threshold of hepatotoxicity.

The simultaneous ingestion of alcohol has been shown to exert a hepatoprotective effect in patients taking massive overdoses of acetaminophen.44,46,51 In one such case, a patient ingested what usually is a lethal dose of 60 g of acetaminophen after 48 hours of heavy drinking of alcohol—and survived with little evidence of hepatotoxicity.52 In this situation, alcohol probably occupied a large proportion of the hepatic CYP2E1, limiting the association of acetaminophen with the enzyme and the subsequent production of NAPQI.36,46,49

With regard to patients with alcoholism taking therapeutic doses of acetaminophen, a review of more 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-control studies) data demonstrated little toxicity with the combination.44,53 On the other hand, some Class III data relying exclusively on patient recall (retrospective case series, single case studies) suggested that "a morbid fate awaits some alcoholic patients who ingest a therapeutic dose of acetaminophen."44 Thus, we are left with conflicting results: well-designed reports suggesting little concern regarding using therapeutic doses of acetaminophen in these patients, and purely retrospective cases suggesting a high likelihood of toxicity. It appears that some patients with alcoholism who ingest massive overdoses of acetaminophen (median dose of 54 g) may be at greater risk of experiencing death than nonalcoholic patients who ingest similar amounts of acetaminophen. The patient with chronic alcoholism may have decreased synthetic rates of a protein transporter that moves glutathione from the hepatic cytosol into the mitochondria. Since the mitochondria are targeted by NAPQI, this may explain the increased toxicity of an acetaminophen overdose in the patient with alcoholism.44 The FDA continues to hold hearings on the issue of alcohol and acetaminophen interactions; it can be hoped that future revisions to its acetaminophen monograph (and, in fact, the monographs for all OTC analgesic agents with respect to alcohol consumption) will be based on evidence and not solely on the results of unsubstantiated case reports.54

Some patients with alcoholism who ingest massive overdoses of acetaminophen may be at greater risk of experiencing death than nonalcoholic patients who ingest similar amounts of acetaminophen.

Corticosteroids. Corticosteroids such as dexamethasone and methylprednisolone are potent anti-inflammatory and immunosuppressant agents. They frequently are used for a host of chronic inflammatory and autoimmune diseases, including asthma, ulcerative colitis and lupus erythematosus and, in combination with other immunosuppressant agents, in the prevention of organ transplant rejection.55 In dentistry, therapeutic uses of glucocorticoids include the reduction of swelling after oral surgery procedures, the treatment of temporomandibular joint syndrome symptoms (often by localized injection), the topical treatment of various oral-mucosal lesions and as "stress steroids" in patients whose hypothalamic-pituitary-adrenal axis is suppressed.55 The actions of corticosteroids on the CYP450 system are complex, and various drugs of the class can act as both substrates and inducers of CYP3A4 isoform5,56 (Tables 1Go and 2Go). As inducers of CYP3A4, these agents could be predicted to be involved in numerous adverse drug interactions,57 in which their concomitant administration would significantly reduce blood levels of many CYP3A4 substrates. However, this prediction has not been borne out in clinical studies.56,57

More important from a clinical perspective is that because corticosteroids are substrates of CYP3A4, their blood levels could become elevated and their half-lives significantly increased when an inhibitor of this enzyme is administered concomitantly. This, in turn, would lead to an increased potential for corticosteroid toxicity, including unwanted immunosuppression, suppression of the hypothalamic-pituitary-adrenal axis and hyperglycemia. The corticosteroid that seems most prone to these interactions is methylprednisolone,58–64 an agent frequently administered in a six-day, 21-dose regimen (a dose-pack) to reduce postoperative swelling after dental impaction surgery. CYP3A4-inhibitor drugs that have been documented to cause the accumulation of methylprednisolone include the macrolide antibiotic drugs erythromycin and clarithromycin,58,59 the azole anti-fungal drugs itraconazole and ketoconazole,60,61 the calcium-channel–blocking agents diltiazem and mibefradil62,63 and 200 mL of double-strength grapefruit juice.64 It is likely that other CYP3A4 inhibitors also could interact adversely with methylprednisolone. Clinicians should be aware of these potential interactions and advise patients to avoid the ingestion of grapefruit juice during their course of methylprednisolone therapy and for at least three days afterward.

Interactions involving CYP450 inducers. Barbiturates. Derivatives of barbituric acid, including phenobarbital and secobarbital, once were important drugs in oral sedation techniques used with anxious dental patients. However, because of their low therapeutic index, high abuse potential, disruptions of rapid-eye-movement–stage sleep and the potential for numerous drug interactions, they have been replaced largely by benzodiazepines.14,65 Barbiturates are known to induce various isoforms of the CYP450 systems, including CYP2C9 and CYP3A4, leading to a decrease in blood levels of a number of drugs. This has been documented for the antidysrhythmic agent quinidine, azole antifungal agents, nifedipine and other calcium-channel blockers, the cancer chemotherapeutic agent etoposide, oral contraceptive agents containing estradiol and progesterone, the immunosuppressant agents cyclosporine and tacrolimus, various HIV protease inhibitors, methadone and warfarin, among others.2,3,66 Acute (single-dose) barbiturate therapy that typically was used in dental sedative techniques probably was only rarely involved in adverse drug interactions involving the induction of the CYP450 system, because induction typically takes at least several days of barbiturate use.2 Longer-term therapy, such as sometimes used for temporomandibular joint dysfunction and headache,67 indeed could cause blood levels of these drugs to fall below therapeutic levels. For example, a patient taking cyclosporine or tacrolimus because of an organ transplant theoretically could experience acute rejection of that organ. Likewise, a patient taking oral contraceptives could begin ovulating and become pregnant while receiving barbiturate therapy. To avoid drug interactions of this type, clinicians also are cautioned to recognize brand-name drugs with "hidden" barbiturate components such as the popular migraine drug Fiorinal (Novartis Pharmaceuticals, East Hanover, N.J.), which contains 325 mg of aspirin plus 50 mg of the barbiturate butalbital.

Clinicians are cautioned to recognize brand-name drugs with ‘hidden’ barbiturate components.

Interactions involving CYP450 inhibitors. Interestingly, the agents used in dental practice that can act as inhibitors of various CYP450 isoforms all are antimicrobial agents. Antimicrobial agents are dosed on a more chronic basis than are other therapeutic agents (such as local anesthetic, analgesic and anxiolytic agents) routinely used in dentistry, which enhances the likelihood of clinically significant CYP450 inhibition and the associated drug interactions with CYP450 substrates.15 These interactions as a whole can be extremely serious and potentially life-threatening if the substrate drug whose metabolism is being inhibited has a low margin of safety or what pharmacologists call a "low therapeutic index."1,15

Quinolone antibiotic agents. Members of the quinolone class include ciprofloxacin, enoxacin, norfloxacin and ofloxacin. Of these agents, the use of systemic ciprofloxacin (typically at a dose of 500 mg twice per day for 10 days) is becoming increasingly popular in the treatment of refractory periodontal infections that harbor Actinobacillus actinomycetemcomitans and other gram-negative, facultatively anaerobic rods.68–70 Ciprofloxacin is a potent inhibitor of CYP1A2 and also produces some inhibition of CYP3A4. The most clinically significant interaction involving ciprofloxacin is its ability to inhibit the metabolism of the CYP1A2 substrate theophylline.71,72 While increases in theophylline blood concentrations and half-life average only about 20 to 30 percent, the drug has a rather low therapeutic index. Cardiac dysrhythmias and convulsions are the most serious consequence of excessive blood levels of theophylline.

It has been reported that a regimen of ciprofloxacin 250 mg taken twice per day for seven days increased average plasma concentrations of the atypical antipsychotic agent clozapine (a CYP1A2 substrate) by approximately 30 percent.73 In one patient, a regimen of ciprofloxacin 500 mg twice per day increased plasma concentrations of clozapine by 80 percent.74 Elevated plasma clozapine levels increase the risk of oversedation, urinary retention, constipation and seizures in a patient population in which noncompliance with schizophrenic medication regimens already is the norm because of the nature of the disease and the unwanted side effects associated with this class of drugs.75

Metronidazole. Metronidazole is highly effective against obligate anaerobic bacteria associated with periodontal disease, periapical abscesses and peri-implantitis.76–79 Because it has no activity against facultative anaerobic bacteria, which can be part of a mixed flora inhabiting these infected sites, metronidazole frequently is combined with a penicillin or with ciprofloxacin.76–78 With respect to drug interactions, metronidazole is best known for its interaction with alcohol. This combination can result in a disulfiram-like reaction, which tends to be more frightening than serious, with patients experiencing nausea, vomiting, headache and cardiac palpitations.15 These symptoms are best explained by metronidazole’s ability to block a key enzyme in alcohol metabolism, namely acetaldehyde dehydrogenase, causing acetaldehyde to accumulate in the bloodstream after alcohol consumption. This adverse drug interaction, however, appears to be unrelated to the inhibition of CYP450 enzymes.

Metronidazole also may be involved in other drug interactions that relate to its ability to inhibit CYP2C9 (Table 3Go). While a number of substrates are metabolized by this isoenzyme, the interaction that appears best documented is the ability of metronidazole to significantly increase the blood concentrations, half-life and the associated hemorrhagic potential of the anticoagulant agent warfarin.80,81 In addition, metronidazole’s ability to cause the accumulation of the antiepileptic drug and CYP2C9 substrate phenytoin is supported by at least one well-designed clinical trial.82 Excessive phenytoin levels in the blood increase the risk of drowsiness, confusion, diplopia, ataxia and nystagmus.83 Before prescribing metronidazole to a dental patient who is receiving chronic warfarin or phenytoin therapy, dentists are advised to consult with the patient’s prescribing physician.

Metronidazole can significantly increase the blood concentrations, half-life and the associated hemorrhagic potential of the anticoagulant agent warfarin.

Macrolide antibiotic agents. Historically, erythromycin was considered to be the antibiotic agent of choice for patients with penicillin allergies who had odontogenic infections.84 However, because of a high incidence of gastrointestinal complaints, increasing bacterial resistance problems and only moderate activity against anerobic bacteria, its use has been decreasing. Clarithromycin is better-tolerated than erythromycin; possesses better activity against most streptococcal, staphylococcal and anaerobic bacterial species; and, while more expensive than erythromycin, may result in better patient compliance because it has to be taken only twice per day.78,84 Like clarithromycin, azithromycin has excellent activity against anaerobes, possesses an extended half-life (requiring only once-per-day dosing) and is an alternative to amoxicillin in patients requiring endocarditis-related prophylaxis who are allergic to penicillins.85 For this indication, both drugs are dosed at 500 mg one hour before the dental procedure.

Erythromycin and clarithromycin are potent inhibitors of CYP3A4 and are associated with numerous untoward drug interactions,2,3,5,8,15 while azithromycin is not.5,86–88 This difference between the macrolides probably is structurally related. Erythromycin and clarithromycin possess 14 carbon atoms surrounding their macrocyclic lactone rings, while azithromycin contains 15 of these constituents.89 The primary reason for the vast number of potential drug interactions with CYP3A4 inhibitors is the fact that CYP3A4 has broad substrate specificity and has been estimated to contribute to the metabolism of more than 50 percent of all available therapeutic agents.57 Since the pharmacokinetic consequences of all these interactions is an accumulation of the substrate drug, side effects of the substrate drug, including relatively rare side effects, become more common and more intense. Typically, the more chronic the dosing with the substrate and the inhibitor, the greater the chance for a clinically significant drug interaction. However, if the substrate undergoes significant (greater than 60 percent) CYP3A4 metabolism in the gut and the liver before reaching the systemic circulation, the likelihood of a significant drug interaction increases, even with just one or two doses of the substrate drug.8 Examples of CYP3A4 substrates with relatively low oral bioavailability include terfenadine, astemizole, simvastatin, lovastatin, felodipine and midazolam.

The ability of erythromycin and clarithromycin to inhibit the CYP3A4-directed metabolism of certain benzodiazepines15–18 and methylprednisolone58,59 already has been discussed. Table 4Go summarizes some additional interactions between CYP3A4 substrates and antimicrobial CYP3A4 inhibitors used in dentistry.86,90–138 Some of these substrates—including the nonsedating antihistamine agents terfenadine and astemizole, the prokinetic agent (gastroesophageal reflux drug) cisapride and the lipid-lowering drug cerivastatin—have been removed from the U.S. market by the FDA, partly because of an unacceptably high incidence of usually rare life-threatening toxicities (torsades de pointes with terfenadine, astemizole and cisapride and rhabdomyolysis with cerivastatin) when administered concomitantly with CYP3A4 inhibitors.


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  		TABLE 4 SOME ADVERSE DRUG:DRUG INTERACTIONS INVOLVING ERYTHROMYCIN, CLARITHROMYCIN, KETOCONAZOLE AND ITRACONAZOLE WITH CYP3A4 SUBSTRATES.

 
Azole antifungal drugs. This group of anti-fungal agents blocks the fungal CYP450-directed synthesis of the cell membrane component ergosterol in sensitive organisms.139 Unfortunately, this mechanism of action leads to inhibition of human CYP450 isoforms, especially CYP3A4. Of this group, ketoconazole and itraconazole are associated with by far the greatest incidence of adverse drug interactions, resulting in the accumulation and subsequent toxicity of a number of CYP3A4 substrates (Table 4Go). Fortunately, these drugs are rarely, if ever, used in outpatient dentistry. However, caution still is advised when administering fluconazole or clotrimazole to treat oral candidiasis in patients taking CYP3A4 substrates. Potentially serious interactions have been reported when these agents are administered to patients taking simvastatin, tacrolimus, warfarin or carbamazepine.108,118,124,131,132


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 CONCLUSIONS
REFERENCES
 
The CYP450 system is responsible for the metabolism of a multitude of diverse pharmacological agents. Drugs routinely used in dentistry often serve as substrates or inhibitors of this system. Dentists can avoid untoward drug interactions in their practices by gaining an understanding of the CYP450 substrates, inducers and inhibitors.


   FOOTNOTES
 

Dr. Hersh is a professor of oral surgery and pharmacology and associate dean of clinical research, University of Pennsylvania School of Dental Medicine, Philadelphia, Pa. 19104-6030, e-mail "evhersh{at}pobox.upenn.edu". 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.


   REFERENCES
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 ABSTRACT
 METHODS
 RESULTS
 CONCLUSIONS
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