Support Care Cancer (2007) 15: 251–257 DOI 10.1007/s00520-006-0127-5

REVIEW ARTICLE

Abdo Haddad Mellar Davis Ruth Lagman

The pharmacological importance of cytochrome CYP3A4 in the palliation of symptoms: review and recommendations for avoiding adverse drug interactions

Received: 2 May 2006 Accepted: 5 July 2006 Published online: 1 December 2006 # Springer-Verlag 2006

M. Davis (*) The Cleveland Clinic Foundation, 9500 Euclid Avenue M76, Cleveland, OH 44195, USA e-mail: [email protected] Tel.: +1-216-4454622 Fax: +1-216-6363179

A World Health Organization demonstration project in palliative medicine. A. Haddad . M. Davis . R. Lagman Palliative Medicine Fellowship Faculty, The Harry R. Horvitz Center for Palliative Medicine, Cleveland Clinic Taussig Cancer Center, Cleveland, OH, USA A. Haddad . M. Davis . R. Lagman The Harry R. Horvitz Center for Palliative Medicine, The Cleveland Clinic Taussig Cancer Center, Cleveland, OH 44195, USA

Abstract Background: Adverse drug interactions are major causes of morbidity, hospitalizations, and mortality. The greatest risk of drug interactions occurs through in the cytochrome system. CYP3A4, the most prevalent cytochrome, accounts for 30–50% of drugs metabolized through type I enzymes. Materials and methods: Palliative patients received medications for

Introduction Advanced cancer patients are on multiple medications for symptom management and co-morbidities [1, 2]. The median number of medications has been reported to be five with a range of 0–13 [1, 2]. Most cancers occur in the elderly who frequently have co-morbidities and are on multiple medications in addition to palliative medications for their cancer, thus increasing risks of drug interactions. Aging influences drug metabolism by reducing cytochrome activity and drug metabolism, thus predisposing to adverse drug interactions. The elderly have a reduction in the volume of distribution of certain medications and organ function that delays drug clearance [2]. Pharmacokinetic drug interactions occur with absorption, drug–protein binding, metabolism, and elimination. By far the most prevalent and dangerous drug–drug interactions occur through cytochrome metabolism [2].

symptoms and co-morbidities, many of which are substrate, inhibitors, or promoters of CYP3A4 activity and expression. A literature review on CYP3A4 was performed pertinent to palliative medicine. Discussion: In this state of the art review, we discuss the CYP3A4 genetics, and kinetics and common medications, which are substrates or inhibitor/promoters of CYP3A4. Conclusion: We made some recommendations for drug choices to avoid clinically important drug interaction. Keywords Adverse drug interactions . Cytochrome system . Cancer patients . Palliative medicine

Drug metabolism is through the cytochrome system (phase I) and/or through conjugation (phase II). Cytochromes oxidize, demethylate, or hydroxylate substrate medications and conjugases increase drug solubility by adding glucuronides, amino acids, or sulfate subgroups that facilitate elimination [3]. Common medications used in palliative medicine (dexamethasone, prednisone, midazolam, triazolam, alprazolam, methadone, fentanyl, and haloperidol) are substrate drugs for CYP3A4. Certain anti-seizure drugs, selective serotonin receptor inhibitors, macrolides, and azoles either upregulate or inhibit CYP3A4 enzyme activity. Protease inhibitors and nucleoside or non-nucleoside analogs used for anti-retroviral therapy can both inhibit enzyme activity and/or upregulate CYP3A4 expression. Typically calcium channel blockers are used for hypertension or arrhythmia, HMG Co A reductase inhibitors for hyperlipidemia, amiodarone for arrhythmia and are metab-

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olized through CYP3A4 and will competitively inhibit or induce CYP3A4 activity. Thus, understanding drug pharmacokinetics and interactions through CYP3A4 is important to palliative specialists to avoid adverse outcomes.

Cytochrome P450 system Medications are metabolized and secreted through the liver, gastrointestinal tract, and kidneys, all of which contain cytochrome enzymes for this purpose. The kidneys do not efficiently eliminate lipophilic drugs that are readily reabsorbed across tubular membranes in the distal renal collecting system; conjugation of drugs improves solubility and drug elimination. Lipid-soluble agents are first metabolized by two reactions termed phase I and phase II before being eliminated. The phase I enzymes most frequently involved are cytochromes CYP3A4/3A5, CYP2D6, CYP2C9, CYP2C19 [4]. Cytochrome-induced oxidation hydroxylation and demethylation proceeds by initial binding of drug to the oxidized form of cytochrome P450, and then coupling NADPH-bound oxygen to the cytochrome P450 oxidoreductase [3].

Cytochrome genetics Individual cytochrome enzyme families are numerically designated (CYP1, CYP2, and CYP3); each family has 40% amino acid homogeneity. Subfamilies are given alphabetical letters (CYP1A, CYP2D, and CYP3A) and have 55% amino acid homogeneity. The particular enzyme is given a number after the letter (CYP1A2, CYP2D6, and CYP3A4 [4–6]. There are over 20 different families in which CYP3A4 accounts for 30% of hepatic cytochrome isoenzymes content and is responsible for metabolizing 50% of medication [7]. The CYP 3A4 gene is found on chromosome 7q at the q21–22 locus [8], and has two 5′ promoter sites that allow for increased enzyme expression through induction [8]. These proximal and distal promoter sites increase enzyme expression; each bind various drugs and transcription factors to increase enzyme expression. Drugs such as dexamethasone, carbamazepine, and methadone are CYP3A4 inducers. Certain inducers such as phenobarbital are not metabolized by CYP3A4 but upregulate CYP3A4 production. CYP3A4 structural polymorphisms are known to exist, but the clinical significance of structural polymorphisms is minor or at least unknown at the present time (unlike CYP2D6). Competitive inhibitors bind to enzyme sites and compete with substrate drugs; the extent of inhibition depends on the substrate drug receptor site affinity (Km) and inhibitor drug affinity for the active enzyme site (Ki). Noncompetitive inhibitors prevent drug metabolism by binding

to sites distant from the active metabolizing site. Uncompetitive inhibitors bind to drug when the drug is in the active enzyme site. Inhibitors and inducers are called precipitant drugs, and substrate drugs whose metabolism is altered are called recipients. Certain drugs permanently bind to active enzymes sites and are called suicide precipitant inhibitors. Suicide inhibitors can cause prolonged inhibition in recipient drug metabolism, which requires enzyme regeneration of CYP3A4 before inhibition is reversed. These mechanistic inhibitors have both a delayed onset of drug interaction and a long inhibitory effect. It is difficult to determine whether clinically significant drug interactions will occur by using in vitro testing. In vitro drug inhibition is dependent on a particular drug probe, drug receptor interaction, and Km, the test system used to determine interactions between medications (microsomal fraction, whole liver, recombinant enzyme) and the recipient probe drug used to test interactions (midazolam, testosterone, quinidine, and nefidipine). The same precipitant drug differentially alters medications metabolized through CYP3A4. For instance, fluvoxamine inhibits methadone clearance through CYP3A4 but not buprenorphine, also a CYP3A4 substrate drug [9]. Metabolites of drugs may be responsible for drug interaction, rather than the parent drug leading to delayed toxicity as the parent drug is metabolized. This may not be observed in in-vitro testing system. The precipitant drug concentration at which 50% of the target cytochrome is inhibited is called the IC50. For competitive inhibitors the inhibitory constant (Ki) is twice the IC50, and for non-competitive inhibitors the IC50 is the Ki. The ratio of the precipitant drug (I) in plasma over the Ki (I/Ki) predicts relatively well the risk for drug interactions. If the ratio is >0.2 [10–12, 47], the drug interactions are likely to be clinically significant. Another way of expressing inhibition is by comparing the change in the area under the curve (AUC) of the recipient drug in the presence and absence of the precipitant drug in vivo. If the AUCi/AUC is greater than 2, then a clinically significant drug inhibition is to be anticipated [13]. CYP3A4 is subject to atypical non-Michaelis–Menten kinetics. Two distinctly different drug-binding sites have been described, and substrate medications may have a particular or preferable binding site. These two binding sites interact when bound by drug, which leads to negative or positive cooperation between binding sites. Depending on the particular enzyme drug-binding site, conformational changes lead to increase or decrease drug clearance relative to dose. Thus, homotropic drug interactions alter drug clearance and precipitant drug interaction [14]. A single-substrate drug for CYP3A4 may promote or inhibit its own metabolism through interactions at both structural enzyme sites and at the promoter site [14]. This nonlinear kinetics adds complexity to predictions of drug interactions. Shared drug metabolism between CYP3A4 and CYP3A5 and with the efflux pump P-glycoprotein adds

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additional complexity to interactions [14]. Finally, plasma concentrations may not predict interactions, as liver concentrations of precipitant drug determine the IC50 and Ki and plasma level will inaccurately predict liver concentration, as many drugs are concentrated in the liver [10]. (See Table 1). Differences in CYP3A4 activity between individuals will vary as much as tenfolds, and 90-fold in CYP3A4 protein expression has been reported using liver samples [7]. CYP3A4 activity is not subject to environmental factors such as smoking and alcohol, but found in extrahepatic sites (kidney, bile duct, GI tract, and brain) and frequently in close proximity to P-glycoprotein combined influences drug bioavailability and regional distribution of CYP3A4-dependent drugs. CYP3A4 varies with gender but not with age. CYP3A4 activity is 25% higher in females [15]. Hepatitis C and B as well as alcoholic liver disease increase CYP3A4 activity.

CYP3A4 substrates (see Table 2) Corticosteroids, opioids (fentanyl, alfentanil, methadone, buprenorphine), benzodiazepines (alprazolam, midazolam, triazolam), neuroleptics, and antidepressants are palliative drugs and CYP3A4 substrates [17]. Drug efficacy and side effects need to be monitored carefully, especially when using CYP3A4 precipitants with these medications (Table 2).

Table 2 CYP3A4 substrates, inhibitors, and inducers [16] CYP3A4 substrates

CYP3A4 inhibitors

CYP3A4 inducers

Benzodiazepines Buprenorphine Buspirone Caffeine Ca channel blocker Codeine Fentanyl

Amiodarone Cimetidine Ciprofloxacin Diltiazem Erythromycin Fluconazole Fluoxetine, fluvoxamine Grapefruit juice Indinavir, nelfinavir, ritonavir, saquinavir Itraconazole

Barbiturates Carbamazepine Dexamethasone Efavirenz Griseofulvin Phenytoin Primidone

Haloperidol HMG Co A reductase Indinavir, nelfinavir, ritonavir, saquinavir Lidocaine Macrolide Methadone Odansetron Quinine Androgenic steroids and corticosteroids Tamoxifen Taxol, vincristine Trazodone Zolpidem

Rifabutin St. John’s wort

Norfloxacin

Haloperidol Haloperidol is commonly used to treat delirium, nausea, and vomiting. Haloperidol is metabolized in the liver by

Table 1 Factors influencing drug interactions of CYP3A4 Factors Recipient drug concentrations Enzyme saturation relative to concentration of recipient drug at enzyme site Substrate drug affinity for the enzyme (Km) and enzyme capacity (Vmax) Homotropic enzyme interactions by recipient drug Concentration of the precipitant drug in liver vs plasma Inhibition constant relative to inhibitor concentration Precipitant drug interactions at both promoter site and the structural enzyme site Liver concentration of precipitant drug and recipient drug Drug (recipient and precipitant drug) clearance through multiple organs or cytochromes Contribution of P-glycoprotein to recipient and precipitant drug metabolism and elimination. Genetically determined expression of CYP3A4 governed by the promoter site.

carbonyl reductase, CYP3A4, and CYP2D6, and secondarily by uridine diphosphoglucose glucuronosyltransferase (UGT) [18]. Haloperidol clearance is mainly through hepatic CYP3A4. Potential drug interactions are reported to occur with phenobarbital, phenytoin, venlafaxine, alprazolam, rifampin, and carbamazepine, but most interactions cause minor changes in haloperidol plasma level, which has little clinical adverse effect partially due to haloperidol’s wide therapeutic index [18]. Carbamazepine decreases haloperidol concentrations by 19 to 100%, depending on the individual, and leads to increased plasma concentrations with discontinuation of carbamazepine. Haloperidol serum levels may rise 500% with carbamazepine discontinuation [18–20]. Selective serotonin receptor inhibitors (SSRI) fluoxetine and venlafaxine increase plasma haloperidol concentrations by blocking CYP2D6 and CYP3A4. Citalopram and sertraline have no effect on haloperidol levels [18, 21–25]. Buspirone, an anti-anxiety medication, is a CYP3A4 inhibitor that will increase haloperidol concentrations. Haloperidol clearance is moderately impaired by the competitive inhibitor alprazolam but not by lorazepam, which is not metabolized through CYP3A4. Grapefruit juice has no influence on haloperidol plasma levels despite inhibition of gastrointestinal CYP3A4. Grapefruit juice does

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not block hepatic CYP3A4, and so haloperidol bioavailability may be increased, but clearance is unaffected [18].

Benzodiazepines CYP3A4 metabolizes alprazolam, midazolam, and triazolam, but not lorazepam, oxazepam, or temazepam. Attention must be paid to the type of benzodiazepine used with CYP3A4 inhibitors, such as macrolides, SSRI, azoles antifungal, or certain inducing antiepileptic drugs.

retroviral medications, methadone should be carefully monitored while patients are on HIV treatment. Buprenorphine is metabolized by CYP3A4, but does not have the same interactions at CYP3A4 as methadone. The parent and metabolite drug norbuprenorphine are rapidly glucuronidated and are inactive even if buprenorphine metabolism is inhibited [31].

CYP3A4 Inhibitor Antifungal medications

Methadone Methadone is subject to dangerous drug interactions at CYP3A4. Methadone is largely metabolized in the liver by CYP3A4 to the N-demethylated derivative EDDP (2ethylidene-1, 5-dimethyl-3, 3-diphenylpyrrolidine). CYP3A4 activity varies considerably between individuals, and this variability is responsible for the large differences in methadone clearance and doses needed for pain relief. Patients on methadone who are also on certain psychotropic drugs, antibiotics, antifungal, macrolides, anticonvulsants or antiretroviral drugs have a significant risk for pharmacokinetic interactions leading to opioid toxicity or withdrawal [26].

Methadone and antibiotics Erythromycin and clarithromycin are potent CYP3A4 inhibitors [27]. The use of these antibiotics should be avoided with patients who are on stable doses of methadone to reduce the risk of opioid toxicity. On the other hand, azithromycin has little interactions with CYP3A4 and is an excellent alternative choice. Ciprofloxacin is commonly used for infections in cancer and is a potent inhibitor to CYP1A2, CYP2D6, and CYP3A4 [28]. Profound sedation is reported with the combination of methadone and ciprofloxacin. Caution should be taken whenever ciprofloxacin is added to steady doses of methadone or fentanyl. Levofloxacin does not significantly interact with CYP3A4 and CYP1A2 and is preferred for those on stable doses of methadone [29, 30].

Methadone and antiretroviral medications Antiretroviral medications are CYP3A4 inducers and inhibitors and will unpredictably alter methadone metabolism. Antiretroviral can cause withdrawal symptoms. As it is impossible to foresee the degree of induction or inhibition from the precipitant antiretroviral in single individuals and patients who are usually on several anti-

Triazoles are used widely in cancer and palliative medicine to treat fungal infections and are potent inhibitors of CYP3A4. Itraconazole is the most potent inhibitor of commonly used triazole. Fluconazole at high doses has the same inhibition as itraconazole. Ketoconazole has the lowest Ki and the greatest inhibition of azoles but is less important because it is infrequently used. Azole antifungals delay the clearance of certain benzodiazepines (diazepam, alprazolam, and midazolam), methadone, and fentanyl. Terbinafine has no significant CYP3A4 interactions and is preferred as an oral antifungal if patients are on CYP3A4 substrates [32]. Voriconazole, one of the newer second-generation triazoles, is primarily metabolized through CYP2C19, and to a lesser extent by CYP2C9 and CYP3A4 [33]. There is no clinically significant interaction between erythromycin, azithromycin and indinavir and voriconazole [34, 35]. Voriconazole is a CYP2C19, CYP2C9, and CYP3A4 substrate, such that multiple drug interactions are potentially possible [36]. Voriconazole inhibits CYP3A4 and thus causes an increase in the maximum concentration (Cmax) and AUC of rifabutin, sirolimus, and astemizole and should be used with caution. Voriconazole increases the Cmax and AUC of cyclosporine, tacrolimus, certain benzodiazepines, as well as HMG-CoA reductase inhibitors, but to a lesser extent than other azoles, such that there is no contraindication, but caution should be taken when these drugs are used with voriconazole. Dose adjustments may need to be made and side effect needs to be monitored [36]. Caspofungin, one of the new antifungals, inhibits cell wall synthesis and has the same efficacy as amphotericin B for candidemia and invasive candidal infections [36]. Caspofungin has a pharmacokinetic advantage, as it is not metabolized through cytochromes [37]. Caspofungin also does not inhibit P-glycoprotein or cytochromes P450 enzymes by in vitro testing, and is a good alternative to fluconazole for certain fungal infection [36]. Cyclosporine increases the AUC of caspofungin by 35%, certain antivirals such as efavirenz, nevirapine, dexamethasone and carbamazepine decrease the AUC of caspofungin and increase its clearance through CYP3A4 [36].

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Macrolide antibiotics Clarithromycin and erythromycin are strong inhibitors of CYP3A4 [28]. Erythromycin induces its own hepatic metabolism into a nitrosoalkane. Nitrosoalkane then forms inactive complexes with the iron in the cytochrome P450 enzyme, and decreases oxidative metabolism of CYP3A4 dependent drugs in a suicide mechanism [27, 38]. Macrolides inhibit CYP3A4 to a variable extent, depending on the macrolide. Macrolides are classified into three groups based on CYP3A4 interactions: 1) Erythromycin strongly binds and inhibits CYP3A4 in a suicide fashion [39]. 2) Clarithromycin has a higher Ki (less affinity and weaker inhibition) than erythromycin. 3) Azithromycin and dirithromycin do not interact with CYP3A4. An additional complicating factor in the use of macrolide is that infections are known to decrease CYP3A4 activity even before antibiotics are instituted [40, 46]. Macrolides further reduce CYP3A4 activity; individuals are particularly prone to drug interactions during sepsis. Clarithromycin and erythromycin increase the bioavailability and AUC (by 60%), and reduce the clearance of midazolam and alprazolam. Macrolides cause opioid toxicity in patients on steady doses of methadone or fentanyl. Azithromycin is preferred, as significant pharmacokinetic interactions do not occur with benzodiazepines [27].

Antidepressant Fluoxetine Fluoxetine is a strong CYP2D6 inhibitor, but also a mild to moderate CYP3A4 inhibitor, and delays clearance of diazepam, alprazolam, methadone, and haloperidol. CYP2D6 is responsible for fluoxetine N-demethylation; CYP2D9, CYP2C19, and CYP3A4 have a lesser role in fluoxetine N-demethylation [9]. Fluvoxamine is a potent CYP3A4 inhibitor [41, 42], whereas paroxetine is a potent CYP2D6 inhibitor, but a weak inhibitor of CYP1A2 and CYP3A4 [42]. Venlafaxine is a weak inhibitor of CYP2D6 and CYP3A4, as is mirtazapine, such that both have a low risk for drug interactions [42]. Sertraline is metabolized by CYP3A4 and inhibits CYP2D6 but not CYP3A4 [9]. Citalopram has minimal to no inhibition of CYP3A4 and is one of the safest SSRIs to use [9]. Grapefruit juice Grapefruit juice is an inhibitor of the intestinal CYP3A4 system, but not the liver CYP3A4 system [42]. Ketoconazole, diltiazem, erythromycin, cyclosporine, and itraco-

nazole inhibit both intestinal CYP3A4 and hepatic CYP3A4, but grapefruit juice inhibits only the intestinal CYP3A4 and will increase bioavailability of CYP3A4 substrate drugs, but not delay clearance [4, 6, 19, 20, 27, 42]. Grapefruit juice increases the bioavailability of certain benzodiazepines, methadone, and statins. Grapefruit juice possibly degrades CYP3A4. Degradation is related to the amount and duration of grapefruit juice exposure [43]. Diltiazem Diltiazem is a calcium channel blocker used in the management of arrhythmia and hypertension. Calcium channel blockers as a class are substrates for CYP3A4. Diltiazem and verapamil also inhibit CYP3A4 and increase the risk of drug–drug interactions with medications metabolized through CYP3A4.

CYP3A4 inducer Glucocorticoids Glucocorticoids accelerate drug clearance by induction of cytochromes, P-glycoprotein, and glucuronosyltransferase [43]. High doses of dexamethasone (16–24 mg/day) promotes CYP3A4 transcription, whereas low doses do not. An 8-mg daily dose of methylprednisolone does not induce CYP3A4 in healthy people [43]. Withdrawal from high doses of glucocorticoids can lead to drug toxicity with CYP3A4 substrate drugs, as CYP3A4 activity will diminish overtime. Carbamazepine Carbamazepine is a potent inducer of CYP3A4 and decreases plasma levels of most CYP3A4 substrates, (methadone, fentanyl, haloperidol). St. John’s Wort Complementary and alternative medicine (CAM) in the US is common. Fifteen million people use herbal preparations in addition to standard prescribed medications [44]. Seven to 64% with cancer use herbal medications [44]. St. John’s Wort is available over the counter and is widely used in Europe and the United States as an antidepressant. St. John’s Wort inhibits the reuptake of noradrenalin, serotonin, and dopamine similar to tricyclic antidepressant, and has a strong affinity to adenosine, gamma aminobutyric acid (GABA), serotonin, and benzodiazepine receptors.

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Table 3 Medication with significant CYP3A4 interaction and safe alternatives [16] Drug group

Medication with CYP3A4 drugs interactions

Alternatives medications

Macrolides Quinolones H2 blockers HMGCo A reductase inhibitors Citrus juice Antidepressants Antifungal

Erythromycin, clarithromycin Ciprofloxacin Cimetidine Simvastatin, lovastatin, atorvastatin Grapefruit juice Fluoxetine, fluvoxamine Fluconazole, itraconazole

Azithromycin Levofloxacin Famotidine, ranitidine fluvastatin, pravastatin Orange juice Venlafaxine, citalopram, mirtazapine Caspofungin

Hyperforin, a component of St. John’s Wort, upregulates CYP3A4. St. John’s Wort reduces methadone or fentanyl analgesia. The combination of St. John’s Wort plus SSRIs increases central nervous system serotonin concentration leading to a serotonin syndrome independent of interactions with CYP3A4 [45]. Patients should be advised not to use St. John’s Wort while on CYP3A4 substrate drugs or SSRIs.

Conclusion Drug interactions are common and dangerous when cytochrome enzymes are involved. CYP3A4 interactions

lead to loss of drug effect or drug toxicity. In vitro drug testing has become a common practice for new drugs and will hopefully predict the risk of drug interaction but should not be dependent on clinical observations that are more important in this regard. Upregulating or inhibiting CYP3A4 occurs through multiple mechanisms. A basic understanding of drug pharmacokinetics will help avoid drug interactions (Table 3). Alternative drugs in each drug class can be chosen, which can reduce the risk of drug interactions. Grapefruit juice should be avoided when taking CYP3A4 substrate drugs. When drug interactions cannot be avoided, close observation and close reduction or titration of the recipient drug may be necessary depending on the precipitant drug.

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