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C L I N I C A L PHARMACOLOGY ABSTRACT
Background. The hepatic and intestinal
cytochrome, or CY, P450
A D A
COVER STORY enzyme system is respon- J
sible for the biotransforma- ✷
✷
N
CON
IO
drugs. Certain medications
T
T
A
used in dentistry can act N
I
in dentistry
C
A UING EDU 1
as substrates, inducers or RT
inhibitors of this system. ICLE
The importance of knowing Methods. The authors
conducted a MEDLINE search of articles
your CYPs appearing between 1976 and the present
using the keywords “drug interactions” and
“cytochrome P450,” and reviewed reports
ELLIOT V. HERSH, D.M.D., M.S., Ph.D.; involving dental therapeutic agents using
PAUL A. MOORE, D.M.D., Ph.D., M.P.H. PubMed links from an Indiana University
TABLE 1
family expressed in the human liver and intes- greatly improved the quality and longevity of life
tine, and thus is involved in the metabolism of a in patients infected with the virus—are sub-
greater number of drugs and a greater proportion strates for CYP3A4.5,6
of adverse drug-drug interactions than are other Inducers of a specific CYP450 isoform (Table 2)
CYP isoforms.4 increase the amount and subsequent activity of
A substrate is a drug or endogenous compound that particular enzyme in hepatic and small
that is metabolized by a particular CYP450 iso- intestinal tissue, potentially leading to dimin-
form. Some substrates for the various CYP450 ished plasma levels of active drugs that are sub-
isoforms are illustrated in Table 1.4,5 For example, strates for that enzyme.2,3,5 In patients with HIV
the HIV protease inhibitors idinavir, nelfinivir, who take protease inhibitors, the concomitant
ritonavir and saquinavir—which, when combined intake of the herbal antidepressant St. John’s
with reverse transcriptase inhibitors, have wort, which is available without a prescription,
TABLE 3
cally can involve inducers and inhibitors of these zolam has been reported to increase the sedative
specific CYP450 isoforms, those involving effects of the benzodiazepine.18 By their ability to
inhibitors of CYP3A4 are of most concern to the inhibit CYP3A4, azole antifungal drugs,4,19-21 pro-
clinician. Like most interactions involving the tease inhibitors (Figure 2),6,16,22 the selective sero-
CYP450 system, interactions involving benzodi- tonin reuptake blocker fluvoxamine and the
azepines are more likely to occur with the oral serotonin-2 receptor antagonist nefezadone (both
administration of these drugs. These particular antidepressants)23 and grapefruit juice24,25 all have
drug interactions have been well-documented; the been shown to significantly increase blood levels,
end result is benzodiazepine accumulation and elimination half-lives and the sedative and
prolonged and excessive sedation.15,16 The psychomotor impairment effects of diazepam,
macrolide antibiotics erythromycin and clar- alprazolam, midazolam and triazolam.
ithromycin, which are used widely in dentistry, Narcotic analgesics. Codeine and tramadol are
are potent inhibitors of CYP3A4. In one placebo- substrates for CYP2D6. They can be prescribed
controlled study,17 erythromycin at 500 mil- for the control of postoperative pain as single
ligrams three times per day for six days increased entities or in combination with aspirin (codeine)
peak blood levels of a single dose of oral mida- or acetaminophen (both codeine and tramadol). In
zolam almost threefold (Figure 1). In addition, the outpatient dental setting, combining mini-
drowsiness and other indicators of psychomotor mally effective doses of these agents (60 mg of
impairment were far more intense in patients codeine or 75 mg of tramadol) with optimal or
taking erythromycin for six days than in those near-optimal doses of aspirin or acetaminophen
taking a placebo.17 Even a single dose of eryth- (600-1,000 mg) usually will provide better anal-
romycin taken concomitantly with oral mida- gesia with fewer side effects than will simply
180 35
N = 12 N = 10
160
(HOURS)
30 (P < .005)
(P = .003)
140
25
120
2
1
ALPRAZOLAM T
100 20
80 15
60
10
40
0 0
Placebo Erythromycin Placebo Ritonavir
DOSE DOSE
Figure 1. Effects of placebo or erythromycin 500 mil- Figure 2. Effects of placebo or the protease inhibitor
ligrams taken three times per day for six days on peak ritonavir on the half-life of alprazolam. Alprazolam’s
plasma levels (mean ± standard error) of a single oral half-life was 13 hours after taking placebo and 30 hours
dose of midazolam 15 mg. Blood levels of midazolam after taking ritonavir (P < .005). Data adapted from
were approximately threefold higher in the erythromycin Greenblatt and colleagues.22
group (P = .003). Data adapted from Olkkola and col-
leagues.17 ng/mL: Nanograms per milliliter.
administering a higher dose of the narcotic high degree of genetic polymorphism.28,30 From a
alone.26,27 Both agents are prodrugs; that is, the clinical perspective, this means that there are
parent compound is essentially devoid of anal- patients in the population who either poorly or
gesic activity but the active demethylated extensively metabolize CYP2D6 substrates. With
metabolites—morphine in the case of codeine and prodrugs like codeine and tramadol, people who
O-demethyl tramadol in the case of tramadol— metabolize them poorly exhibit little analgesic
are responsible for the analgesic activity.28,29 The activity with the intake of these drugs because
CYP450 isoform responsible for this conversion is they do not form the necessary active metabolites,
CYP2D6 (Figure 3). It has been demonstrated while people who metabolize them extensively
with both drugs that the administration of the readily form the active metabolites and exhibit
antidysrhythymic agent quinidine, a known significant analgesia.28 Up to 10 percent of the
CYP2D6 inhibitor, essentially abolishes their white population are thought to metabolize
analgesic activity.28,30 Other widely prescribed CYP2D6 substrates poorly.5 While this issue is
CYP2D6 inhibitors—including antidepressant outside the scope of clinical practice, it is possible
agents of the selective serotonin reuptake that in the future, a simple blood test for CYP2D6
inhibitor class (fluoxetine, paroxetine and sertra- activity could be used to predict a patient’s likely
line) and the cyclo-oxygenase-, or COX-, 2– response to either agent.
selective nonsteroidal anti-inflammatory drug, or Lidocaine. Lidocaine, the most frequently used
NSAID, celecoxib—have the theoretical potential local anesthetic in all of dentistry, is a substrate
to diminish the analgesic effects of both codeine for both CYP2D6 and CYP3A4.5 Because two
and tramadol. The clinical significance of these CYP450 isoforms control the drug’s metabolism,
interactions needs to be explored. dramatic increases in lidocaine blood levels are
One other intriguing discovery with important unlikely to occur by the inhibition of a single
clinical implications is that CYP2D6 exhibits a isoform (for example, inhibition of CYP3A4 by
OH OH
CYP2D6 CYP2D6
CH3O O HO O CH3O HO
Codeine Morphine
Tramadol O-Demethyl Tramadol
A B
Figure 3. The demethylation of selected prodrugs to the active metabolites morphine and O-demethyl tramadol by
CYP2D6. A. Codeine. B. Tramadol.
erythromycin). Four doses of erythromycin ethyl- and an increased likelihood of toxicity. However,
succinate 600 mg given over two days modestly it appears that other CYP450 isoforms also play a
increased the half-life of an intravenous lidocaine role in NSAID metabolism,38-40 so that inhibitors
31
infusion from 2.2 to 2.8 hours. Of interest to of the single CYP2C9 isoform should not cause
pediatric dentists, who frequently use antihis- dramatic increases in blood levels or half-lives of
tamines in sedative premedication regimens, the these NSAIDs, especially after short-term dosing
CYP2D6 inhibitors diphenhydramine and chlor- for acute pain.
rospective case series, single case studies) sug- dicted to be involved in numerous adverse drug
gested that “a morbid fate awaits some alcoholic interactions,57 in which their concomitant admin-
patients who ingest a therapeutic dose of istration would significantly reduce blood levels of
acetaminophen.”44 Thus, we are left with con- many CYP3A4 substrates. However, this predic-
flicting results: well-designed reports suggesting tion has not been borne out in clinical studies.56,57
little concern regarding using therapeutic doses of More important from a clinical perspective is
acetaminophen in these patients, and purely ret- that because corticosteroids are substrates of
rospective cases suggesting a high likelihood of CYP3A4, their blood levels could become elevated
toxicity. It appears that some patients with alco- and their half-lives significantly increased when
holism who ingest massive overdoses of an inhibitor of this enzyme is administered con-
acetaminophen (median dose of 54 g) may be at comitantly. This, in turn, would lead to an
greater risk of experiencing death than nonalco- increased potential for corticosteroid toxicity,
holic patients who ingest similar amounts of including unwanted immunosuppression, sup-
acetaminophen. The patient with chronic alco- pression of the hypothalamic-pituitary-adrenal
holism may have decreased synthetic rates of a axis and hyperglycemia. The corticosteroid that
protein transporter that moves glutathione from seems most prone to these interactions is methyl-
the hepatic cytosol into the mito- prednisolone,58-64 an agent fre-
rhythmic agent quinidine, azole antifungal 500 mg twice per day for 10 days) is becoming
agents, nifedipine and other calcium-channel increasingly popular in the treatment of refrac-
blockers, the cancer chemotherapeutic agent tory periodontal infections that harbor Acti-
etoposide, oral contraceptive agents containing nobacillus actinomycetemcomitans and other
estradiol and progesterone, the immunosuppres- gram-negative, facultatively anaerobic rods.68-70
sant agents cyclosporine and tacrolimus, various Ciprofloxacin is a potent inhibitor of CYP1A2 and
HIV protease inhibitors, methadone and war- also produces some inhibition of CYP3A4. The
farin, among others.2,3,66 Acute (single-dose) barbi- most clinically significant interaction involving
turate therapy that typically was used in dental ciprofloxacin is its ability to inhibit the
sedative techniques probably was only rarely metabolism of the CYP1A2 substrate theo-
involved in adverse drug interactions involving phylline.71,72 While increases in theophylline blood
the induction of the CYP450 system, because concentrations and half-life average only about 20
induction typically takes at least several days of to 30 percent, the drug has a rather low thera-
barbiturate use.2 Longer-term therapy, such as peutic index. Cardiac dysrhythmias and convul-
sometimes used for temporomandibular joint dys- sions are the most serious consequence of exces-
function and headache,67 indeed sive blood levels of theophylline.
could cause blood levels of these It has been reported that a reg-
This adverse drug interaction, however, appears Erythromycin and clarithromycin possess 14
to be unrelated to the inhibition of CYP450 carbon atoms surrounding their macrocyclic lac-
enzymes. tone rings, while azithromycin contains 15 of
Metronidazole also may be involved in other these constituents.89 The primary reason for the
drug interactions that relate to its ability to vast number of potential drug interactions with
inhibit CYP2C9 (Table 3). While a number of sub- CYP3A4 inhibitors is the fact that CYP3A4 has
strates are metabolized by this isoenzyme, the broad substrate specificity and has been esti-
interaction that appears best documented is the mated to contribute to the metabolism of more
ability of metronidazole to significantly increase than 50 percent of all available therapeutic
the blood concentrations, half-life and the associ- agents.57 Since the pharmacokinetic consequences
ated hemorrhagic potential of the anticoagulant of all these interactions is an accumulation of the
agent warfarin.80,81 In addition, metronidazole’s substrate drug, side effects of the substrate drug,
ability to cause the accumulation of the including relatively rare side effects, become more
antiepileptic drug and CYP2C9 substrate pheny- common and more intense. Typically, the more
toin is supported by at least one well-designed chronic the dosing with the substrate and the
clinical trial.82 Excessive phenytoin levels in the inhibitor, the greater the chance for a clinically
blood increase the risk of drowsi- significant drug interaction. How-
TABLE 4
* 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.
CYP450 isoforms, especially CYP3A4. Of this substrates (Table 4). Fortunately, these drugs are
group, ketoconazole and itraconazole are associ- rarely, if ever, used in outpatient dentistry. How-
ated with by far the greatest incidence of adverse ever, caution still is advised when administering
drug interactions, resulting in the accumulation fluconazole or clotrimazole to treat oral candidi-
and subsequent toxicity of a number of CYP3A4 asis in patients taking CYP3A4 substrates.
Potentially serious interactions have been 19. Yasui N, Kondo T, Otani K, et al. Effect of itraconazole on the
single oral dose pharmacokinetics and pharmacodynamics of alpra-
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avoided in patients receiving the systemic antimycotics ketoconazole or
or carbamazepine.108,118,124,131,132 itraconazole. Clin Pharmacol Ther 1994;55:481-5.
21. Varhe A, Olkkola KT, Neuvonen PJ. Oral triazolam is potentially
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