Trilafon

The basic purpose of drug metabolism in the body is to make drugs more water soluble and thus more readily excreted in the urine or bile.[1,2] One common way of metabolizing drugs involves the alteration of functional groups on the parent molecule (e.g., oxidation) via the cytochrome P450 enzymes. These enzymes are most predominant in the liver but can also be found in the intestines, lungs and other organs.[3-6] These cytochrome P450 enzymes are designated by the letters "CYP" followed by an Arabic numeral, a letter and another Arabic numeral (e.g., CYP2D6).[7] Each enzyme is termed an isoform since each derives from a different gene. It should be noted, however, that structural similarity of enzymes cannot be used to predict which isoforms will be responsible for a drug's metabolism.

Drug interactions involving the cytochrome P450 isoforms generally result from one of two processes, enzyme inhibition or enzyme induction. Enzyme inhibition usually involves competition with another drug for the enzyme binding site. This process usually begins with the first dose of the inhibitor,[8,9] and onset and offset of inhibition correlate with the half-lives of the drugs involved.[9]

Enzyme induction occurs when a drug stimulates the synthesis of more enzyme protein,[9] enhancing the enzyme's metabolizing capacity. It is somewhat difficult to predict the time course of enzyme induction because several factors, including drug half-lives and enzyme turnover, determine the time course of induction.

Illustrative Case 1

A 74-year-old woman with insulin-dependent (type 2) diabetes had been taking metoprolol and warfarin for atrial fibrillation and amitriptyline, 50 mg at bedtime, for diabetic neutopathy, for several years. On the death of her husband, she presented with symptoms of depression, and paroxetine was added to her medication regimen with the rationale that paroxetine would cause fewer side effects than an increase in the amitriptyline dosage. Three days after the initiation of paroxetine therapy, the woman was brought to the emergency department by her daughter, who had found her asleep at 11 a.m. On awakening, the patient complained of dry mouth and dizziness. The emergency department physician, noting that paroxetine had recently been added to the medication regimen, changed the patient to fluoxetine, which he thought would be less sedating. Three days later, the patient was still very sedated and dizzy, and complained of difficulty urinating. She was again brought to the emergency department, where bladder catheterization yielded two liters of dark urine. Her International Normalized Ratio (INR) was 4.0.

On discussion with a colleague, the emergency department physician learned that both paroxetine and fluoxetine can inhibit cytochrome P450 enzymes (isoforms) responsible for the metabolism of the patient's other medications. This example illustrates the need to understand the cytochrome P450 isoforms responsible for drug metabolism and their inhibitors and inducers.

Cytochrome P450 isoforms CYP2D6

CYP2D6 has been studied extensively because it exhibits genetic polymorphism, meaning that distinct population differences are apparent in its expression or activity. Approximately 7 to 10 percent of Caucasians are poor metabolizers of drugs metabolized by CYP2D6.[10] Individuals with normal CYP2D6 activity are termed extensive metabolizers. Ethnic differences are indicated in this genetic polymorphism, since Asians and blacks are less likely than Caucasians to be poor metabolizers.[11,12] Poor metabolizers are at risk for drug accumulation and toxicity from drugs metabolized by this isoform. For example, one patient who suffered cardiotoxicity induced by desipramine (Norpramin) was found to be a poor metabolizer.[13] Poor metabolizers of CYP2D6 substrates are at risk for postural hypotension and antipsychotic side effects such as oversedation, because several antipsychotic agents are metabolized by CYP2D6.[14] In a study of 45 elderly patients five of whom were poor metabolizers) receiving perphenazine, side effects increased fivefold in the poor metabolizers compared with the extensive metabolizers.[15] Conversely, when formation of an active metabolite is essential for drug action, poor metabolizers of CYP2D6 can exhibit less response to drug therapy compared with extensive metabolizers. Codeine is O-demethylated to morphine by CYP2D6, which accounts at least partially for its analgesic effect.[16] Thus, poor metabolizers may have less response to codeine than other persons. The substrates and inhibitors of CYP2D6 are fisted in Table 1.

TABLE 1 Substrates and Inhibitions of CYP2D6

Substrates Antidepressants(*)

Amitriptyline (Elavil)

Clomipramine (Anafranil)

Desipramine (Norpramin)

Doxepin (Adapin, Sinequan)

Fluoxetine (Prozac)

Imipramine (Tofranil)

Nortriptyline (Pamelor)

Paroxetine (Paxil)

Venlafaxine (Effexor) Antipsychotics

Haloperidol (Haldol)

Perphenazine (Etrafon, Trilafon)

Risperidone (Risperdal)

Thioridazine (Mellaril) Beta blockers

Metoprolol (Lopressor)

Penbutolol (Levatol)

Propranolol (Inderal)(*)

Timolol (Blocadren) Narcotics

Codeine, tramadol (Ultram)

Inhibitors Antidepressants

Paroxetine > fluoxetine >

sertraline (Zoloft) > fluvoxamine

(Luvox),

Nefazodone (Serzone),

Venlafaxine > clomipramine

(Anafranil) > amitriptyline Cimetidine (Tagamet) Fluphenazine (Prolixin) Antipsychotics

Haloperidol

Perphenazine

Thioridazine

(*) -- Other enzymes are also involved. NOTE: inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).

Psychotherapeutic Agents. Many antidepressants are metabolized by CYP2d6, but other cytochrome P450 isoforms can also contribute to their metabolism (Tables 1 through 6). The clinical importance of this "dual metabolism" will be illustrated later. With respect to drugs inhibiting CYP2D6, cimetidine (Tagamet), the selective serotonin reuptake inhibitors (SSRIs) and some tricyclic antidepressants function as inhibitors of this P450 isoform.[17-19] Of the antidepressants, paroxetine Paxil) appears to have the greatest ability to inhibit the metabolism of CYP2D6 substrates. This is followed by fluoxetine (Prozac) and norfluoxetine; sertraline Zoloft) and desmethylsertraline; fluvoxamine Luvox), nefazodone (Serzone) and venlafaxine (Effexor); clomipramine (Anafranil), and amitriplyline (Elavil).[19] This ranking is based on in vitro data, however, and the choice of an antidepressant should be based on factors other than the propensity to inhibit CYP2D6. Although sertraline appears to be less likely than the other SSRIs to inhibit CYP2D6, inhibition may still occur at doses greater than 50 mg. The clinical significance of the inhibition of tricyclics by SSRIs or cimetidine is subject to variation in enzyme activity between individuals, the degree to which the patient metabolizes and co-ingestion of other enzyme inhibitors.[20]

TABLE 2 Substrates, Inhibitors and Inducers of CYP3A

Substrates Amitriptyline(*) (Elavil) Benzodiazepines

Alprazolam (Xanax)

Triazolam (Halcion)

Midazolam (Versed) Calcium blockers Carbamazepine (Tegretol) Cisapride (Propulsid) Dexamethasone (Decadron) Erythromycin Ethinyl estradiol (Estraderm, Estrace) Glyburide (Glynase, Micronase) Imipramine(*) (Tofranil) Ketoconazole (Nizoral) Lovastatin (Mevacor) Nefazodone (Serzone) Terfenadine (Seldane) Astemizole (Hismanal) Verapamil (Calan, Isoptin) Sertraline (Zoloft) Testosterone Theophylline(*) Venlafaxine (Effexor) Protease inhibitors

Ritonavir (Norvir)

Saquinavir (Invirase)

Indinavir (Crixivan)

Nelfinavir (Viracept)

Inhibitors Antidepressants

Nefazodone > fluvoxamine (Luvox) > fluoxetine

(Prozac) > sertraline

Paroxetine (Paxil)

Venlafaxine Azole antifungals

Ketoconazole (Nizoral) > itraconazole (Sporanox)

> fluconazole (Diflucan) Cimetidine (Tagamet)[dagger] Clarithromycin (Biaxin) Diltiazem Erythromycin Protease inhibitors

Inducers Carbamazepine Dexamethasone Phenobarbital Phenytoin (Dilantin) Rifampin (Rifadin, Rimactane)

(*) -- Other enzymes are involved. [dagger -- Does not inhibit a CYP3A substrates, does not inhibit terfenadine metabolism, NOTE: Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect unless the substrate is a prodrug), inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).

TABLE 3 Substrates, Inhibitors and Inducers of CYP1A2

Substrates Amitriptyline(*) (Elavil) Clomipramine (Anafranil)(*) Clozapine (Clozaril)(*) Imipramine (Tofranil)(*) Propranolol (Inderal)(*) R-warfarin(*) Theophylline(*) Tacrine (Cognex)

Inhibitors Fluvoxamine (Luvox) Grapefruit juice Quinolones

Ciproflaxacin (Cipro)

Enoxacin (Penetrex) > norfloxacin (Noroxin) >

ofloxacin (Fioxin) > lomefloxacin (Maxaquin)

Inducers Omeprazole (Prilosec) Phenobarbital Phenytoin (Dilantin) Rifampin (Rifadin, Rimactane) Smoking Charcoal-broiled meat,

(*) -- other enzymes involved. NOTE: Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).

TABLE 4 Substrates, Inhibitors and Inducers of CYP2E1

Substrates Acetaminophen (Tylenol) Ethanol

Inhibitors Disulfiram (Antabuse)

Inducers Ethanol Isoniazid (Laniazid)

NOTE: inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect unless the substrate is a prodrug).

TABLE 5 Substrates, Inhibitors and Inducers of CYP2C9

Substrates Nonsteroidal anti-inflammatory drugs Phenytoin (Dilantin) S-warfarin Torsemide (Demadex)

Inhibitors Fluconazole (Diflucan) Ketoconazole (Nizoral) Metronidazole (Flagyl) Itraconazole (Sporanox) Ritonavir (Norvir)

Inducers Rifampin (Rifadin, Rimactane)

NOTE:Inhibitors will decrease metabolism of substrates and generally lead to increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).

TABLE 6 Substrates and Inhibitors of CYP2C19

Substrates Clomipramine (Anafranil)(*) Diazepam (Valium)(*) Imipramine (Tofrani)(*) Omeprazole (Prilosec) Propranolol (Inderal)(*) Inhibitors Fluoxetine (Prozac) Sertraline (Zoloft) Omeprazole Ritonavir (Norvir)

(*) -- Other enzymes involved also. NOTE: Inhibitors will decrease metabolism of substrates and generally lead to Increased drug effect (unless the substrate is a prodrug). Inducers will increase metabolism of substrates and generally lead to decreased drug effect (unless the substrate is a prodrug).

CYP3A

Inhibitors of CYP3A. Members of the CYP3A subfamily are the most abundant cytochrome enzymes in humans. They account for 30 percent of the cytochrome P450 enzymes in the liver[21] and are also substantially expressed in the intestines. Members of this subfamily are involved in many clinically important drug interactions.[1] Substrates, inhibitions and inducers of CYP3A are listed in Table 2.

Nonsedating Antihistamines. High plasma concentrations of terfenadine (Seldane) and astemizole (Hismanal) have been associated with torsade de pointes, a life-threatening cardiac arrhythmia characterized by altered cardiac repolarization and a prolonged QT interval.[22] Terfenadine is a prodrug that undergoes complete first-pass metabolism to an active carboxymetabolite.[23] It is therefore unusual to detect terfenadine in the plasma of patients who take this drug at the recommended dosage. Since it is terfenadine rather than its active metabolite that is cardiotoxic, arrhythmias occur when a build-up of parent terfenadine takes place. This may occur when azole antifungal medications or macrolide antibiotics are taken concomitantly.[22,24] To counteract this problem, fexofenadine (Allegra), the active metabolite of terfenadine, is now marketed as a noncardiotoxic alternative to terfenadine. Like fexofenadine, loratadine (Claritin) does not appear to be cardiotoxic and thus is also a safe nonsedating antihistamine alternative.[25]

Ketoconazole (Nizoral), itraconazole (Sporanox) and fluconazole (Diflucan) inhibit CYP3A, although ketoconazole and itraconazole are more inhibiting than fluconazole.[26] Based on in vitro and in vivo studies, ketoconazole and itraconazole markedly inhibit metabolism of terfenadine, causing changes in the QT interval.[22,27] At dosages of 200 mg daily, fluconazole did not result in accumulation of parent terfenadine or changes in the QT interval.[28] However, an interaction with terfenadine and fluconazole coadministration may occur in patients taking higher dosages of fluconazole or in patients with risk factors for ventricular arrhythmia. These two drugs should be used together with caution.

In addition to the azole antifungal medications, the macrolide antibiotics can also inhibit terfenadine metabolism, resulting in the development of torsade de pointes. Erythromycin and clarithromycin (Biaxin) have been shown to alter terfenadine metabolism, but this does not appear to occur with azithromycin (Zithromax).[29] Thus, a patient who is taking terfenadine and needs macrolide antibiotic therapy should be given azithromycin to avoid possible cardiac consequences.

The SSRIs are 28 to 775 times less potent as inhibitors of terfenadine metabolism than ketoconazole.[30] With respect to ability to inhibit CYP3A, the following order of the SSRIs is observed: nefazodone is greater than fluvoxamine, and norfluoxetine is greater than fluoxetine, which is greater than sertraline, desmethylsertraline, paroxetine and venlafaxine.[31] Several clinically important cardiac events have been reported in patients receiving fluoxetine or fluvoxamine with terfenadine or astemizole.[30,32,33] The use of fluvoxamine or nefazodone with terfenadine or astemizole is contraindicated, and the U.S. Food and Drug Administration is currently considering requiring a contraindication against the use of other SSRIs with the nonsedating antihistamines.[30] The package insert for sertraline contains a warning against its use with terfenadine and astemizole.[34] In patients who need to take an antidepressant and a nonsedating antihistamine concurrently, paroxetine, venlafaxine and tricyclic antidepressants may be safe options, since they inhibit CYP3A more weakly.[35,36] Conversely, fexofenadine or loratadine, neither of which are associated with arrhythmias, could be prescribed, thus permitting more freedom in the choice of an antidepressant.

Cisapride. Serious ventricular arrhythmias have been reported in patients taking cisapride (Propulsid) and drugs that inhibit CYP3A, the isoform responsible for metabolism of cisapride.[37] Ketoconazole, fluconazole, itraconazole, metronidazole, erythromycin and clarithromycin have been associated with cisapride-induced torsade de pointes.[37] Concurrent use of cisapride with fluoxetine, sertraline, fluvoxamine and nefazodone might be problematic because of CYP3A inhibition.[38]

Theophylline. Erythromycin[39] and clarithromycin[40] (but not azithromycin[41]) decrease theophyuine metabolism by inhibiting CYP3A. The interaction between erythromycin and theophylline is most likely to occur in patients receiving higher dosages of erythromycin and increases with the duration of therapy.

Inducers of CYP3A. Because of the resurgence of tuberculosis in the United States, rifampin (Rifadin, Rimactane), an inducer of the CYP3A subfamily, is being prescribed more widely than in previous years. Of particular clinical relevance is the potential reduction of oral contraceptive efficacy by rifampin, since estradiol levels can be reduced by rifampin-mediated CYP3A induction.[42] In addition to rifampin, potent glucocorticoids such as dexamethasone (Decadron) are also inducers of CYP3A, but lower-potency glucocorticoids, such as prednisolone, have minimal effect.43

CYP1A2

CYPIA2 can be induced by exposure to polycyclic aromatic hydrocarbons, such as those found in charbroiled foods and cigarette smoke.[44] This is the only P450 isoform affected by tobacco. Cigarette smoking can result in an increase of as much as threefold in CYPIA2 activity.[44] Theophylline is metabolized in part by CYPIA2,[45] which explains why smokers require higher doses of theophynine than nonsmokers. Table 3 lists the substrates, inhibitors and inducers of CYP1A2.

Quinolones. Certain quinolone antibiotics can inhibit theophylline metabolism,[46-48] although this effect is highly variable. The interaction between enoxacin (Penetrex) or ciprofloxacin (Cipro) and theophynine[47] is most significant in patients with plasma theophylline concentrations at the upper end of normal. Conversely, norfloxacin (Noroxin) and ofloxacin (Floxin) have little effect on theophylline concentrations,[46] and lome-floxacin (Maxaquin) does not appear to alter the pharmacokinetics of theophylhne.[49] Since cimetidine is an inhibitor of CYPIA2,[17] additive inhibition of theophylline metabolism occurs when cimetidine is combined with a fluoroquinolone.

CYP2E1

This isoform is inducible by ethanol and isoniazid and is responsible in part for the metabolism of acetaminophen.[50]) The product of acetaminophen's cytochrome P450 metabolism is a highly reactive intermediate that must be detoxified by conjugation with glutathione.[51] Patients with alcohol dependence may be at increased risk for acetaminophen hepatotoxicity because ethanol induction of CYP2E1 increases formation of this reactive intermediate, and glutathione concentrations are decreased in these patients.52 Cimetidine exhibits only moderate affinity for this isoform and produces no significant inhibition of the production of acetaminophen's toxic metabolite.[17] Table 4 lists the substrates, inhibitors and inducers of CYP2E1.

CYP2C9

S-Warfarin. Warfarin is produced as a racemic mixture of R-warfarin and S-warfarin, but the predominance of pharmacologic activity resides in the S-enantiomer.[53] Most metabolism of S-warfarin is by means of CYP2C9,[54] and inhibition of this isoform results in several clinically important drug interactions. Fluconazole, metronidazole, miconazole and amiodarone are a few examples of the many drugs that profoundly inhibit S-warfarin metabolism and produce marked increases in prothrombin time measurements.[55-58] Interestingly, cimetidine, a very weak inhibitor of CYP2C9,[17] has been shown to have very little effect on warfarin concentrations.[59] The substrates, inhibitors and inducers of CYP2C9 are listed in Table 5.

Phenytoin. Phenytoin is primarily metabolized via CYP2C9,[6O] although CYP2C19 may also play a small role.61 As stated above, cimetidine is a weak inhibitor of CYP2C9. It is most likely to cause clinically significant inhibition of phenytoin metabolism at cimetidine dosages greater than 1,200 mg in patients at the upper end of the phenytoin therapeutic range.[62] In patients with nonlinear metabolism of phenytoin at relatively low serum levels, the risk of interaction with cimetidine is increased. However, it is difficult to identify these patients in a clinical situation.

CYP2C19

Like CYP2D6, CYP2C19 has been shown to exhibit genetic polymorphism.[63,64] This enzyme is completely absent in 3 percent of Caucasians and 20 percent of Japanese. Drugs metabolized by this isoform include omeprazole Prilosec),[65] lansoprazole (Prevacid)[66] and diazepam (Valium).[67] However, clinical examples of excessive or adverse drug effects in people who are CYP2C19-deficient are lacking. Table 6 lists the substrates and inhibitors of CYP2C19.

Illustrative Case 2

A 47-year-old man recently diagnosed with HIV infection visited his physician with flushing, dizziness and swelling of the feet and ankles. He had been taking sustained-release nifedipine for treatment of hypertension for about three years. Approximately two weeks earlier, his physician had prescribed a combination of lamivudine, zidovudine and the protease inhibitor ritonavir.

The HIV-1 protease inhibitors ritonavir, indinavir, saquinavir and nelfinavir all inhibit the CYP3A subfamily of enzymes, thus increasing the serum levels of other drugs that are metabolized by this pathway, including nifedipine. It is likely that the addition of ritonavir to this patient's medical regimen resulted in an increase in the serum level of nifedipine and the subsequent symptoms of flushing and dizziness. Of the currently available protease inhibitors, ritonavir, because of its ability to both inhibit and induce CYP450 enzymes, is associated with the most drug-drug interactions.[68]

Final Comment

Physicians who become familiar with the role of the various cytochrome P450 enzymes in drug metabolism can often predict the consequences of drug interactions and explain patients' responses to medication regimens. Although tests for isoform expression are not widely available, it is conceivable that such testing may become standard practice in the future, given the clinical importance of isoform deficiencies. In the future, testing may help to identify individuals at risk for drug interactions and adverse events.

REFERENCES

[1.] Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes, Ann Pharmacother 1995.29:619-24.

[2.] Gram TE. Metabolism of drugs. In: Craig CR, Stitzel RE, eds. Modern pharmacology. 4th ed. Boston: Little, Brown, 1994:33-46.

[3.] Guengerich FP. Catalytic selectivity of human cytochrome P450 enzymes: relevance to drug metabolism and toxicity. Toxicol Lett 1994;70:1 33-8.

[4.] Kolars JC, Lown KS, Schmiedlin-Ren P, Ghosh M, Fang C, Wrighton SA, et al. CYP3A gene expression in human gut epithelium. Pharmacogenetics 1994;4:247-59.

[5.] Wheeler CW, Guenthner TM. Spectroscopic quantitation of cytochrome P-450 in human lung microsomes. J Biochem Toxicol 1990;5:269-72.

[6.] Philpot RM. Characterization of cytochrome P450 in extrahepatic tissues. Meth Enzymology 1991. 206:623-31.

[7.] Nelson DR, Kamataki T, Waxman DJ, Guengerich FP, Estabrook RW, Feyereisen R, et al. The P450 superfamily: update on new sequences, gene mapping, accession numbers, early trivial names of enzymes, and nomenclature. DNA Cell Biol 1993; 12:1-51.

[8.] Murray M, Reidy GF. Selectivity in the inhibition of mammalian cytochromes P-450 by chemical agents. Pharmacol Rev 1990.42:85-101.

[9.] Dossing M, Pilsgaard H, Rasmussen B, Poulsen HE. Time course of phenobarbital and cimetidine mediated changes in hepatic drug metabolism. Eur J Clin Pharmacol 1983;25:215-22.

[10.] Steiner E, Bertilsson L, Sawe J, Bertling 1, Sjoqvist F Polymorphic debrisoquin hydroxyiation in 757 Swedish subjects. Clin Pharmacol Ther 1988. 44:431-5.

[11.] Relling MV, Cherrie J, Schell M), Petros WP, Meyer WH, Evans WE. Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects. Clin Pharmacol Ther 1991.50:308-13.

[12.] Bertilsson L, Lou YQ, Du YL, Liu Y, Kuang TY, Liao XM, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992;51: 388-97 [Published erratum appears in Clin Pharmacol Ther 1994;55:648].

[13.] Spina E, Ancione M, Di Rosa AE, Meduri M, Caputi AP. Polymorphic debrisoquine oxidation and acute neuroleptic-induced adverse effects, Eur J Clin Pharmacol 1992;42:347-8.

[14.] Cholerton S, Daly AK, Idle JR. The role of individual human cytochromes P450 in drug metabolism and clinical response. Trends Pharmacol Sci 1992.13: 434-9.

[15.] Pollock BG, Mulsant BH, Sweet RA, Rosen J, Altieri LP, Perel JM. Prospective cytochrome P450 phenotyping for neuroleptic treatment in dementia. Psychopharmacol Bull 1995;31:327-31.

[16.] Yue QY, Svensson JO, Alm C, Sjoqvist F, Sawe J. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br J Clin Pharmacol 1989;28:639-45.

[17.] Knodell RG, Browne DG, Gwozdz GP, Brian WR, Guengerich FR Differential inhibition of individual human liver cytochromes P-450 by cimetidine. Gastroenterology 1991;101:1680-91.

[18.] Philip PA, James CA, Rogers HJ. The influence of cimetidine on debrisoquine 4-hydroxylation in extensive metabolizers. Eur I Clin Pharmacol 1989.36:319-21.

[19.] Crewe HK, Lennard MS, Tucker GT, Woods FR, Haddock RE. The effect of selective serotonin re-uptake inhibitors on cytochrome P4502D6 (CYP2D6) activity in human liver microsomes. Br J Clin Pharmacol 1992.34:262-5.

[20.] Tollefson GD. Adverse drug reactions/interactions in maintenance therapy. J Clin Psych 1993;54 Suppl):48-60.

[21.] Shimada T, Yamazaki H, Mimura M, Inul Y, Guengerich FP. Interindividual variations in human liver cytochrome P-450 enzymes involved in the oxidation of drugs, carcinogens and toxic chemicals: studies with liver microsomes of 30 Japanese and 30 Caucasians. J Pharmacol Exp Ther 1994;270:414-23.

[22.] Honig PK, Wortham DC, Zamani K, Conner DP, Mullin JC, Cantilena LR. Terfenadine-ketoconazole interaction. Pharmacokinetic and electrocardiographic consequences. JAMA 1993.269:1513-8 [Published erratum appears in JAMA 1993;269:20881.

[23.] Garteiz DA, Hook RH, Walker BJ, Okerholm RA. Pharmacokinetics and biotransformation studies of terfenadine in man. Arzneimittel-Forschung 1982; 32:1185-90.

[24.] Honig PK, Woosley RL, Zamani K, Conner DP, Cantilena LR Jr. Changes in the pharmacokinetics and electrocardiographic pharmacodynamics of terfenadine with concomitant administration of erythromycin. Clin Pharmacol Ther 1992;52:231-8.

[25.] Haria M, Fitton A, Peters DH. Loratadine. A reappraisal of its pharmacological properties and therapeutic use in allergic disorders. Drugs 1994.48:617-37.

[26.] von MoIke LL, Greenblatt DJ, Schmider J, Duan SX, Wright CE, Harmatz JS, et al. Midazolam hydroxylation by human liver microsomes in vitro: inhibition by fluoxetine, norfluoxetine, and by azole antifungal agents. J. Clin Pharmacol 1996;36:783-91.

[27.] Honig PK, Wortham DC, Hull R, Zamani K, Smith JE, Cantilena LR. Itraconazole affects single-dose terfenadine pharmacokinetics and cardiac repolarization pharmacodynamics. J Clin Pharmacol 1993; 33:1201-6.

[28.] Honig PK, Wortham DC, Zamani K, Mullin JC, Conner DP, Cantilena LR. The effect of fluconazole on the steady-state pharmacokinetics and electrocar-diographic pharmacodynamics of terfenadine in humans. Clin Pharmacol Ther 1993;53:630-6.

[29.] Honig PK, Wortham DC, Zamani K, Cantilena LR. Comparison of the effect of the macrolide antibiotics erythromycin, clarithromycin and azithromycin on terfenadine steady-state pharmacokinetics and electrocardiographic parameters. Drug Invest 1994;7:148-56.

[30.] Solvay's Luvox contraindication against co-administration with J&J's Hismanal, MMD's Seldane prompts FDA review of other SSRI labeling. FDC Reports: the Pink Sheet 1995:26-9.

[31.] Ketter TA, Flockhart DA, Post RM, Denicoff K, Pazzaglia PJ, Marangell LB, et al. The emerging role of cytochrome P450 3A in psychopharmacology. J Clin Psychopharmacol 1995; 15:387-98,

[32.] Marchiando RJ, Cook MD, Jue SG. Probable terfenadine-fluoxetine-associated cardiac toxicity [Letter), Ann Pharmacother 1995;29:937-8.

[33.] Swims MR Potential terfenadine-fluoxetine interacton [Letter]. Ann Pharmacother 1993.27:1404-5.

[34.] Pfizer, Inc. Package insert. Zoloft (sertraline). New York: 1996.

[35.] von MoItke LL, Greenblatt DJ, Court MH, Duan SX, Harmatz JS, Shader RI. Inhibition of alprazolam and desipramine hydroxylation in vitro by paroxetine and fluvoxamine: comparison with other selective serotonin reuptake inhibitor antidepressants. J Clin Psychopharmacol 1995;15:125-31.

[36.] von Moltke LL, Duan SX, Greenblatt DJ, Fogelman SM, Schmider J, Harmatz JS, et al. Venlafaxine and metabolites are very weak inhibitors of human cytochrome P450-3A isoforms. Biol Psychiatry 1997;41:377-80.

[37.] Wysowski DK, Bacsanyl J. Cisapride and fatal arrhythmia [Letter]. N Engl J Med 1996.335:290-1.

[38.] Caley C Cisapride interaction with antidepressants [Letter] Ann Pharmacother 1996;30:684.

[39.] Cummins LH, Kozak PP Jr, Gillman SA, Erythromycin's effect on theophylline blood level. Pediatrics 1977.59:144.

[40.] Ruff F, Chu SY, Sonders RC, Senello LT. Effect of multiple doses of clarithromycin on the pharmacokinetics of theophylline [Abstract]. Thirtieth Inter-science Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C.: American Society for Microbiology, 1990:761.

[41.] Hopkins S. Clinical toleration and safety of azithromycin. Am I Med 1991.91 40S-5S.

[42.] Bolt HM, Kappus H, Remmer H. Studies on the metabolism of ethynylestradiol in vitro and in vivo: the significance of 2-hydroxylation and the formation of polar products. Xenobiotica 1973. 3:773-85.

[43.] Schuetz EG, Wrighton SA, Barwick JL, Guzelian PS. Induction of cytochrome P-450 by glucocorticoids in rat liver. 1. Evidence that glucocorticoids and pregnenolone 16 alpha-carbonitrile regulate de novo synthesis of a common form of cytochrome P450 cultures of adult rat hepatocytes and in the liver in vivo. J Biol Chem 1984;259:1999-2006.

[44.] Pelkonen O, Pasanen M, Kuha H, Gachalyi B, Kairaluoma M, Sotaniemi EA, et al. The effect of cigarette smoking on 7-ethoxyresorufin O-deethylase and other monooxygenase activities in human liver: analyses with monoclonal antibodies. Br J Clin Pharmacol 1986;22:125-34.

[45.] Sarkar MA, Jackson BJ. Theophylline N-demethylations as probes for P4501A1 and P4501A2. Drug Metab Dispos 1994;22:827-34.

[46.] Radandt JM, Marchbanks CR, Dudley MN. Interactions of fluoroquinolones with other drugs: mechanisms, variability, clinical significance, and management. Clin infect Dis 1992;14:272-84.

[47.] Wijnands WJ, Vree TB, van Herwaarden CL. The influence of quinolone derivatives on theophylline clearance. Br J Clin Pharmacol 1986;22:677-83.

[48.] Sarkar M, Polk RE, Guzelian PS, Hunt C, Karnes HT In vitro effect of fluoroquinolones on theophylline metabolism in human liver microsomes. Antimicrob Agents Chemother 1990.34:594-9.

[49.] Parent M, LeBel M. Meta-analysis of quinoonetheophylline interactions. Ann Pharmacother 1991. 25:191-4.

[50.] Raucy JL, Lasker JM, Lieber CS, Black M Acetaminophen activation by human liver cytochromes P450lIE1 and P450IA2. Arch Biochem Biophys 1989.271:270-83,

[51.] Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, Brodie BB. Acetaminophen-induced hepatic necrosis V Protective role of glutathione. J Pharmacol Exp Ther 1973; 187:211-7.

[52.] Loguercio C, Piscopo P, Guerriero C, De Girolamo V, Disalvo D, Del Vecchio Blanco C. Effect of alcohol abuse and glutathione administration on the circulating levels of glutathione and on antipyrine metabolism n patients with alcoholic liver cirrhosis. Scand J C in Lab Invest 1996.56:441-7.

[53.] O'Reilly RA. Studies on the optical enantiomorphs of warfarin in man. Clin Pharmacol Ther 1974; 16:348-54.

[54.] Rettie AE, Korzekwa KR, Kunze KL, Lawrence RF, Eddy AC, Aoyama T, et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 n the etiology of (S)-warfarin-drug interactions. C hem Res Toxicol 1992, 5:54-9.

[55.] Black DJ, Kunze KL, Wienkers LC, G da BE, Seaton TL, McDonnell ND, et al. Warfarin-fluconazole. II A metabolically based drug interaction: in vivo studies. Drug Metab Dispos 1996.24 422-8

[56.] O'Reilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med 1976;295:354-7.

[57.] O'Reilly RA, Goulart DA, Kunze KL, Neal J, Gibaldi M, Eddy AC, et al. Mechanisms of the stereoselective interaction between miconazole and racemic warfarin in human subjects. Clin Pharmacol Ther 1992;51:656-67.

[58.] Heimark LD, Wienkers L, Kunze K, Gibaldi M, Eddy AC, Trager WF, et al. The mechanism of the interaction between amiodarone and warfarin in humans. Clin Pharmacol Ther 1992;51:398-407.

[59.] Niopas I, Toon S, Rowland M. Further insight into the stereoselective interaction between warfarin and cimetidine in man. Br J Clin Pharmacol 1991;32:508-11.

[60.] Veronese ME, Mackenzie PI, Doecke CJ, McManus ME, Miners JO, Birkett DJ. Tolbutamide and phenytoin hydroxylations by cDNA-expressed human liver cytochrome P4502C9. Biochem Biophys Res Commun 1991;175:1112-8 [Published erratum appears in Biochem Biophys Res Commun 1991;1 80:1527).

[61.] Levy RH. Cytochrome P450 isozymes and antiepileptic drug interactions. Epilepsia 1995;36 Suppl 5):S8-13.

[62.] Bartle WR, Walker SE, Shapero T Dose-dependent effect of cimetidine on phenytoin kinetics. Clin Pharmacol Ther 1983;33:649-55.

[63.] Wedlund PJ, Aslanian WS, McAllister CB, Wilkinson GR, Branch RA. Mephenytoin hydroxylation deficiency in Caucasians: frequency of a new oxidative drug metabolism polymorphism. Clin Pharmacol Ther 1984;36:773-80.

[64.] Nakamura K, Goto F, Ray WA, McAllister CB, Jacqz E, Wilkinson GR, et al. Interethnic differences in genetic polymorphism of debrisoquin and mephenytoin hydroxylation between Japanese and Caucasian populations. Clin Pharmacol Ther 1985. 38:402-8.

[65.] Andersson T, Miners JO, Veronese ME, Tassaneeyakul W, Meyer UA, Birkett DJ. identification of human liver cytochrome P450 isoforms mediating omeprazole metabolism. Br J Clin Pharmacol 1993;36:521-30.

[66.] Pearce RE, Rodrigues AD, Goldstein JA, Parkinson A. Identification of the human P450 enzymes involved in lansoprazole metabolism. J Pharmacol Exp Ther 1996;277:805-16.

[67.] Jung F, Richardson TH, Raucy JL, Johnson EF Diazepam metabolism by cDNA-expressed human 2C P450s: identification of P4502C18 and P4502C 19 as low K(M) diazepam N-demethylases. Drug Metab Dispos 1997;25:133-9.

[68.] Deeks SG, Smith M, Holodniy M, Kahn JO. HIV-1 protease inhibitors. A review for clinicians. JAMA 1997.277:145-53.

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