Many patients with pain are prescribed multiple

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1 PAIN MEDICINE Volume 10 Number S Opioid Metabolism and Effects of Cytochrome P450 Gregory L. Holmquist, PharmD Group Health, Seattle, Washington, Palliative Care Strategies, Bothell, Washington, USA ABSTRACT Over the past years researchers have enhanced our understanding of the metabolism and risk of drug interactions of numerous medications utilized by patients with pain conditions. Pain patients often are prescribed multiple medications that can inhibit or induce specific cytochrome P450 (CYP450) enzymes. This review will focus on the effect of the CYP450 enzyme system metabolism on opioid agents codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone, as well as the potential effect of these opioids on the metabolism of other medications and vice versa. Key Words. Cytochrome P450; Drug Interactions; CYP3A4; CYP2D6; Metabolites; Opioids Reprint requests to: Gregory L. Holmquist, PharmD, Group Health, Seattle, Washington, Palliative Care Strategies, Bothell, Washington, th Dr SE, Bothell, Washington 98021, USA. Tel: ; Fax: ; Introduction Many patients with pain are prescribed multiple pharmacological interventions, often administered concurrently. Polypharmacy, a term that describes the use of multiple medications in patients [1], can be a concern due to overlapping toxicities and increased risk of drug drug interactions secondary to altered metabolism. Some data suggest that the risk of a drug drug interaction increases with number of medications used, occurring in 13% of patients taking two medications and 82% of patients taking more than six medications [2]. It has been estimated that 75% of adverse reactions are related to interactions that increase or decrease the amount or action of the drug in the body by the presence of another drug or multiple drugs affecting its metabolism [3]. Over the past years, researchers have enhanced our understanding of the metabolism and risk of drug interactions of numerous medications utilized by patients with pain conditions. While much of the research has focused on tricyclic antidepressants, selective serotonin reuptake inhibitor antidepressants, first-generation anticonvulsants (e.g., carbamazepine and phenytoin), and methadone, recently there has been a heightened interest in the unique and specific metabolism and thereby potential drug interaction risks of various opioid agents. An understanding of the metabolism of opioids will assist practitioners in avoiding clinically significant and dangerous interactions. This review will focus on the effect of the cytochrome P450 (CYP450) enzyme system metabolism on opioid agents such as codeine, fentanyl, hydrocodone, hydromorphone, methadone, morphine, oxycodone, and oxymorphone, as well as the potential effect of these opioids on the metabolism of other medications and vice versa. CYP450 Enzyme System All opioids are metabolized through two major enzyme systems, CYP450 and, to a lesser extent, by the UDP-glucuronosyltransferases (UGTs) with a specific affinity for the UGT2B7 isozyme. The UGTs are a secondary metabolizing system responsible for the formation of glucuronides and have a major role in the metabolism of hydromorphone, morphine, and oxymorphone. The CYP450 system is of major significance in the metabolism of codeine, fentanyl, methadone, oxycodone, and oxymorphone. As will be discussed later, due to genetic variation in CYP450 and to the potential for drug interactions, these later five agents have significant risks for wide serum level variation. CYP450 enzymes are present in many tissues of the body, including the endoplasmic reticula in American Academy of Pain Medicine /09/$15.00/S20 S20 S29 doi: /j x

2 Effects of CYP450 on Opioid Agents hepatocytes, intestinal mucosa, lungs, brain, and kidney [4]. Essential for the production of cholesterol, steroids, prostacyclins, and thromboxane A 2, cytochrome Ps (CYPs) are the major enzymes involved in drug metabolism, accounting for approximately 75% of the total metabolism of all drugs [5]. The active site of cytochrome P450 contains a heme center. Their name is derived from being bound to membranes within a cell (cyto) and contain a heme pigment that absorbs light at a wavelength of 450 nm (chrome) when exposed to carbon monoxide [6]. Researchers have discovered more than 50 CYP450 enzymes, but the CYP1A2, CYP2C9, CYP2D6, CYP3A4, and CYP3A5 enzymes account for the metabolism of up to 90% of drugs that undergo this type of biotransformation [7,8]. Substances that interact with the CYP450 system usually do so in one of three ways: 1) by acting as a substrate; 2) through inhibition; or 3) through induction (Table 1). A drug can at the same time be a substrate for and induce or inhibit one or more CYP450 enzymes. Coadministered drugs that share the same metabolic pathway (i.e., are substrates for the same CYP450 enzymes) may compete with each other. One drug may be competitively stronger in affecting metabolism and thereby garner more enzyme activity, and lead to a diminishing of the metabolism of the other drug and intensify its pharmacological effects. Additionally, a drug can be both metabolized by and inhibit the same enzyme, or it can be metabolized by one enzyme and inhibit another enzyme [6]. Table 2 provides examples of medications that can inhibit or induce specific CYP450 enzymes and medications that are often prescribed (substrates) for chronic pain patients and may be affected. Table 1 Definitions [3,9 11] Substrate Inhibitor Inducer Any drug metabolized by one or more CYP450 enzymes. A drug that slows the activity of a specific CYP450 enzyme metabolism of a substrate for those particular enzymes. The effect often leads to excessively high serum drug levels and potential toxic effects. Process usually begins with the first dose of the inhibitor and duration correlates with the half-lives of the drugs involved. A drug that boosts the activity of a specific CYP450 enzyme metabolism of a substrate for those particular enzymes. This effect often leads to lower than expected serum drug levels and a reduced effect of the drug. Time course is difficult to predict. Can be affected by drug half-lives and enzyme turnover. CYP450 = cytochrome P450. Genetic Polymorphism S21 Genetic polymorphism (i.e., distinct population differences that are apparent in its expression or activity) occurs with all CYP450 enzymes, but appears to be the greatest with CYP2D6. The CYP2D6 gene is highly polymorphic, with 100 allelic variants identified [15]. Allele combinations determine four major CYP2D6 phenotypes: poor metabolizers (PM), intermediate (IM), extensive metabolizers (EM), and ultrarapid metabolizers (UM). Individuals with normal CYP2D6 activity are termed EM. Estimates by researchers suggest that 7 10% of Caucasians are PM of drugs that utilize the CYP2D6 pathway [16]. There are large interethnic differences in the frequencies of the variant alleles. Ethnic differences have been identified in studies demonstrating that Asians and African Americans are less likely than Caucasians to be PM [17,18]. PM are at risk for drug accumulation and toxicity from drugs metabolized by this isoform. On the other hand, PM of CYP2D6 can exhibit less response to drug therapy compared with EM when the formation of an active metabolite is essential for drug action (e.g., the chief analgesic effect of codeine is due to O-demethylation to the active metabolite morphine via CYP2D6 and thus, poor metabolizers may have less response to codeine than other persons). A number of studies suggest that there are significant pharmacokinetic and pharmacodynamic differences between PM and EM patients with opioid agents that undergo metabolism via the CYP2D6 system such as codeine [19 33], hydrocodone [34], methadone [35], and oxycodone [36,37]. In addition to genetic polymorphism reported with CYP2D6, CYP3A4 as the most abundant metabolic enzyme in the body can vary 30-fold between individuals in terms of its presence and activity in the liver [38]. This enzyme is also found in the gastrointestinal tract, so metabolism of substrates utilizing this isoform can be initiated prior to the drug entering the circulatory system. Also, the amount of CYP3A4 in the intestine can exhibit genetic variation of up to 11-fold, leading to variance in the breakdown and absorption of some substrates. Although there is genetic variability of the UGT enzyme 2B7, the in vitro and in vivo functional significance of these variants is not well defined [15]. Additionally, genetic variability studies related to UGT metabolism of morphine has not been shown to alter levels of the production of its chief metabolites nor change the

3 S22 Holmquist Table 2 Examples of cytochrome P450 enzymes and associated inhibitors, inducers, and substrates that may be prescribed for pain patients [12 14] Enzyme Substrate Inhibitor* Inducer CYP2D6 CYP2C9 CYP3A4 Amitriptyline Amphetamine Codeine Desipramine Dextromethorphan Donepezil Doxepin Duloxetine Fluoxetine Haloperidol Hydrocodone Methadone Metoclopramide Nortriptyline Ondansetron Oxycodone Paroxetine Promethazine Risperidone Tramadol Venlafaxine Amitriptyline Celecoxib Diclofenac Fluoxetine Ibuprofen Meloxicam Naproxen Phenytoin Piroxicam Warfarin Alprazolam Buspirone Codeine Dexamethasone Diazepam Fentanyl Haloperidol Hydrocodone Lidocaine Methadone Protease inhibitors Testosterone Tramadol Trazodone Venlafaxine Zaleplon Ziprasidone Zolpidem Amiodarone Bupropion Celecoxib Cimetidine Citalopram Diphenhydramine Doxepin Duloxetine Escitalopram Fluoxetine Haloperidol Hydroxyzine Methadone Paroxetine Ritonavir Sertraline Venlafaxine Amiodarone Fluconazole Fluoxetine Ketoconazole Itraconazole Lovastatin Metronidazole Ritonavir Sertraline Trimethoprin/sulfa Cimetidine Diazepam Erythromycin Fluoxetine Fluconazole Grapefruit juice Itraconzole Ketoconazole Nefazodone Protease inhibitors Venlafaxine Verapamil No significant inducers. Carbamazepine Phenobarbital Phenytoin Rifampin Carbamazepine Dexamethasone Phenobarbital Phenytoin Rifampin St. John s Wort * Medications that slow down substrate drug metabolism and increase drug effect. Medications that speed up substrate drug metabolism and decrease drug effect. efficacy of patient response to analgesia from morphine [39,40]. Hydromorphone, Morphine, Oxymorphone, and the UGT System The chief metabolic pathways, metabolites and the potential role of codeine, fentanyl, hydrocodone, hydromorphone, methadone, oxycodone, and oxymorphone as substrates, inhibitors, or inducers of CYP450 are outlined in Table 3. As noted, hydromorphone, morphine and oxymorphone are not metabolized by CYP450 enzymes to any great extent; therefore, inhibition/induction or genetic polymorphisms of CYP450 enzymes should have little to no effect on the metabolism or clearance of these agents. The chief pathway of these three agents is the UGT 2B7 metabolic pathway that

4 Effects of CYP450 on Opioid Agents S23 Table 3 Opioid metabolism [15,38,41 51] Drug Chief pathways of metabolism Metabolites Codeine O-demethylation via CYP2D6. Glucuronidation by UGT2B7. Morphine* Norcodeine Normorphine Hydrocodeine Codeine-6-glucuronide* Codeine-3-glucuronide Fentanyl N-demethylation via CYP3A4. Norfentanyl Despropionylfentanyl Hydroxyfentanyl Hydroxynorfentanyl Hydrocodone O-demethylation via CYP2D6. N-demethylation via CYP3A4. Hydromorphone Glucuronidation by UGT2B7 and UGT1A3. Methadone N-demethylation via CYP3A4. O-demethylation via CYP2D6. Other CYP450: CYP2C8, 2C9, 2C19, 2B6, and 1A2. Morphine Glucuronidation by UGT2B7 and 1A3. Oxycodone O-demethylation via CYP2D6. N-demethylation via CYP3A4. Glucuronidation by UGT2B7. Hydromorphone* Norcodeine Norhydrocodone 6-alpha- & 6-beta-hydrocodol 6-alpha & 6-beta-hydromorphol Hydromorphone-3-glucuronide Hydromorphone-3-glucoside Dihydroisomorphine-6-glucuronide Dihydroisomorphine-6-glucoside Dihydroisomorphine Dihydromorphine EDDP (2-ethyl-1,5-dimethyl-3-3- diphenylpyrrolimium) EMDP (2-ethyl-5-methyl-3,3- diphenylpyraline Morphine-3-glucuronide Morphine-6-glucuronide* Normorphine 7,8-dihydromorphinone Noroxycodone Noroxymorphone Oxymorphone* Oxycodyl a and b Oxymorphol a and b Oxycodol a and b Noroxymorphone Oxymorphone Glucuronidation by UGT2B7. Oxymorphone-3-glucuronide Hydroxyoxymorphone * Active metabolites. Toxic metabolite. CYP = cytochrome P450; UGT = UDP-glucuronosyltransferases. Role as substrate, inhibitor, or inducer of CYP450 Comments Substrate, levels could be altered by inhibitors of CYP2D6 Substrate of UGT2B7 Genetic polymorphisms of CYPs may influence metabolism and production of active metabolites and thus affect therapeutic efficacy Substrate, levels could be altered by inhibitors and inducers of CYP3A4. Genetic polymorphisms of CYPs may influence metabolism and therapeutic efficacy and toxicity Substrate, levels could be altered by inhibitors of CYP2D6 Genetic polymorphisms of CYPs may influence metabolism and therapeutic efficacy and toxicity Not a substrate, inhibitor, or inducer of CYP Substrate of UGT2B7 Genetic polymorphisms of UGT enzymes exist, no evidence to suggest variability alters metabolism to affect efficacy or toxicity Substrate, levels could be altered by inhibitors and inducers of CYP3A4, 2D6, and 2C9 May act as a weak inhibitor of CYP2D6. Not a substrate, inhibitor or inducer of CYP A substrate of UGT 2B7 Substrate, levels could be altered by inhibitors and inducers of CYP3A4 and 2D6. A substrate of UGT2B7 Genetic polymorphisms of CYPs may influence metabolism and account for reported large variability of serum levels for a given dose in different subjects Genetic polymorphisms of UGT enzymes exist, no evidence to suggest variability alters metabolism to affect efficacy or toxicity Genetic polymorphisms of CYPs may influence metabolism and thus therapeutic efficacy or toxicity Not a substrate, inhibitor or inducer of CYP A substrate of UGT2B7 Genetic polymorphisms of UGT enzymes exist, no evidence to suggest variability alters metabolism to affect efficacy or toxicity

5 S24 chiefly forms glucuronides. The glucuronidation process typically inactivates drugs; however, extensive research with morphine has suggested that the two chief metabolites of morphine, morphine-3- glucuronide (M3G) (representing about 50 60% of the total metabolites) and morphine-6- glucuronide (M6G) (representing about 10% of the total metabolites), have potential for significant clinical effects. M3G has no analgesic properties but may have central nervous system (CNS) toxicity that includes irritability, hallucinations, and allodynia [41,47]. M6G is an active metabolite, exhibiting up to a 50-fold greater potency than the parent drug morphine in its analgesic properties [41,47]. Most hydromorphone is glucuronidated at the 3-carbon position to form hydromorphone-3-glucuronide (H3G) via the UGT enzymes 1A3 and 2B7 [46]. The pharmacological activity of H3G in humans has not been established, but in rats it has been shown to be excitatory and can lead to seizures [52]. Oxymorphone is metabolized in a similar manner as hydromorphone, without any significant CYP450 involvement. The UGT metabolites of oxymorphone do not appear to be active or toxic. Theoretically, inhibiting UGT 2B7 could decrease morphine s activity, since M6G levels would be decreased. Also, inducing UGT 2B7 could theoretically increase the toxicity of morphine and hydromorphone by increasing the levels of the 3-glucuronide metabolite of each drug. Induction of UGT 2B7 could also decrease the efficacy of morphine, hydromorphone, and oxymorphone by enhancing the metabolism and thereby decreasing the levels of the active parent drug. The UGT enzymes are not as well studied as the CYP450 enzymes, and there are few welldesigned drug drug interaction studies with morphine, and no published studies with hydromorphone or oxymorphone with inhibitors or inducers of UGT 2B7. Fromm et al. [53] published the results of a small double-blind, placebo-controlled crossover study of patients who received morphine and were exposed to rifampin, an inducer of UGT 2B7. After rifampin exposure, the area under curve (AUC) of morphine, M3G, and M6G decreased and pain thresholds became similar to placebo. Although the study suggested that rifampin did decrease the efficacy of morphine, the decrease in AUC of UGT metabolites M3G and M6G led to the conclusion that mechanisms other than induction of UGT enzymes played a role. The effect of ranitidine, an inhibitor of UGT2B7, was studied by Aasmundstad and Storset [54] in eight health patients receiving morphine concurrently. The results of this double-blind, placebo-controlled, crossover study demonstrated that ranitidine decreased the serum M3G and M6G ratio and increased the AUC of morphine. The authors concluded that these results suggested evidence of ranitidine being an inhibitor of UGT2B7. There was no outcome analysis regarding clinical efficacy or toxicity of this interaction with morphine. In contrast to the lack of CYP450 metabolism for hydromorphone, morphine, and oxymorphone, several other opioid agents (i.e., codeine, fentanyl, hydrocodone, methadone, and oxycodone) rely extensively on CYP450 for their activation or inactivation. Codeine, hydrocodone, methadone, and oxycodone are subject to significant O-demethylation catalyzed by CYP2D6. Fentanyl and methadone are subject to significant N-dealkylation or N-demethylation, respectively, catalyzed by CYP3A4. Some metabolites of opioids generated through the CYP450 system have activity themselves (e.g., morphine as the metabolite of codeine is thought to be chiefly responsible for its analgesic activity, hydrocodone s metabolite hydromorphone represents at least a portion of its analgesic activity, and oxymorphone, an active metabolite of oxycodone, is responsible for some component of oxycodone s analgesic capabilities). While it has been postulated that codeine s main activity is via its metabolic biotransformation to morphine [55], some researchers suggest that a significant portion of codeine s analgesic activity is through the biotransformation to codeine-6-glucuronide via the UGT 2B7 enzyme system. While there are numerous studies suggesting the role of CYP2D6 in the biotransformation of codeine into the active form morphine [19 33], there are no studies or case reports suggesting that inhibition or induction of UGT2B7 alters codeine s efficacy. Thus it appears that the risks of significant drug interactions associated with codeine are those that inhibit or induce the CYP2D6 enzyme. Hydrocodone Holmquist Hydrocodone is a semisynthetic opioid, structurally related to codeine. Hydrocodone undergoes CYP450 dependent metabolism via both the CYP2D6 and CYP3A4 enzymes. The chief metabolites are thought to be the O-demethylated active metabolite hydromorphone and the N-demethylated inactive metabolite norhydroc-

6 Effects of CYP450 on Opioid Agents odone. Like codeine, some researchers have proposed that hydrocodone is a prodrug. The mu-opioid receptor binding affinity of hydromorphone is 30 times greater than that of hydrocodone and has been suggested to contribute to the therapeutic efficacy and side effects of the parent drug [43]. Although few studies have provided definitive proof, it is possible that drugs that inhibit or induce CYP2D6 or patients that are PM or UM could alter the efficacy of hydrocodone. There is neither evidence nor theoretical basis for concern that drugs that affect CYP3A4 would have any impact on the efficacy or the toxicity of hydrocodone. Oxycodone Oxycodone has a similar structure to hydrocodone, but the parent drug is a potent analgesic in its own right. While oxycodone is not a prodrug, metabolism via CYP2D6 does create an active metabolite, oxymorphone. Other routes of metabolism include CYP3A4 to noroxycodone and glucuronidation via UGT 2B7. None of the metabolites appear to be toxic. For years, many clinicians and researchers have thought that oxymorphone that is formed from O-demethylation by CYP2D6 represented the principal activating pathway, a situation analogous to the bioconversion of codeine to morphine or hydrocodone to hydromorphone. However, animal and human studies have demonstrated that inhibition of oxymorphone formation by the CYP2D6-selective inhibitor quinine or quinidine did not decrease the antinociceptive effect of oxycodone in rats [56], nor attenuate the opioid side effects of oral oxycodone in human volunteers, despite a 50-fold reduction in oxymorphone AUC [57]. Lalovic et al. [44] investigated the pharmacokinetics and pharmacodynamics of oxycodone in healthy human subjects. These researchers concluded that CYP3A4-mediated N-demethylation is the principal metabolic pathway of oxycodone in humans and that the central opioid effects of oxycodone are governed by the parent drug, with a negligible contribution from its circulating oxidative and reductive metabolites. Regardless of which CYP450 enzyme system is responsible for the major pathway of oxycodone s clearance, there is concern that toxicity could occur in patients receiving oxycodone who exhibit genetically poor CYP2D6 or CYP3A4 metabolism or in situations in which patients are coadministered an inhibitor of one of these enzymes such as fluoxetine, paroxetine, sertraline, venlafaxine, and grapefruit juice, among others. One published postmortem retrospective analysis of 15 deaths where suspected oxycodone was a cause of death reported that two and as many as six deaths occurred in patients with poor CYP450 2D6 metabolism [58]. Fentanyl S25 The synthetic opioid fentanyl undergoes extensive metabolism in humans. The major route of metabolism is N-dealkylation to norfentanyl. None of the fentanyl metabolites possess significant pharmacological activity [59]. As discussed earlier, CYP3A4 is the most abundant metabolic enzyme in the body and can vary 30-fold between individuals in terms of its presence and activity in the liver [38]. This enzyme is also found in the gastrointestinal tract, so metabolism of substrates utilizing this isoform can be initiated prior to the drug entering the circulatory system. Also, the amount of this enzyme in the intestine can exhibit genetic variation of up to 11-fold, leading to variance in the breakdown and absorption of some substrates. Thus, genetic variation, as well as drugs that inhibit or induce CYP3A4, may increase or decrease the oral bioavailability of swallowed fentanyl from oral transmucosal (OTF) dosage forms. Patients who begin or end therapy with potent inhibitors of CYP3A4 such as macrolide antibiotics, azole fungal agents, and protease inhibitors while receiving oral OTF agents should be monitored for a change in opioid effects, and if warranted, the dose should be adjusted. Kharasch et al. [60] concluded from a study in 12 healthy volunteers that alterations in intestinal or hepatic CYP3A4 activity had little influence on OTF absorption and onset of effect, but did alter fentanyl elimination and duration of effect. The authors further concluded that OTF drug interactions are unlikely to alter the onset or magnitude of analgesia, but duration may be affected. In a review published by Labroo et al. [50], the authors concluded that it is more difficult to predict the impact of variable hepatic CYT3A4 expression on intersubject variability in the systemic clearance of intravenous and transdermal fentanyl, as well as the incidence and severity of CYT3A4-mediated drug interactions. The authors made this conclusion based on the fact that fentanyl is a high extraction drug and therefore, theoretically, relatively insensitive to changes in hepatic intrinsic clearance caused by altered CYP3A4 activity. However, the author did further state that the effects of altered

7 S26 hepatic CYP3A4 activity on systemic fentanyl elimination are unknown and that additional investigations are required to characterize more fully the clinical implications of fentanyl metabolism by CYP3A4 in liver, intestine, and other organs. Methadone Holmquist Methadone is a synthetic opioid structurally dissimilar to other opioids discussed in this paper. The clinically used rac-methadone is a mixture of (R)- and (S)-enantiomers in which the (R)-methadone is the major pharmacologically active form. The affinity of (R)-methadone for mu- and delta-opioid receptors and its analgesic activity are 10- and 50-fold higher, respectively, compared with those of (S)-methadone [42]. With a unique pharmacokinetic and pharmacodynamic profile, research has established that the metabolism of methadone is affected by multiple CYP450 enzymes, including CYP3A4 [38,42,45,49,51,61], CYP2D6 [38,42,45,49,51,61], CYP 2C8 [42,51], CYP 2C9 [38,45,49,51], CYP 2C19 [38,45,49,51], CYP 2B6 [45,49,51] and CYP1A2 [38,45,49,51,61]. While the chief metabolite of methadone EDDP (2-ethyl- 1,5-dimethyl-3-3-diphenylpyrrolimium) and other minor metabolites are neither toxic nor active, inhibition and induction of the metabolism of methadone poses significant risks to patients. Many commonly prescribed medications inhibit CYP2D6 and CYP3A4 enzymes, leading to clinically significant higher serum blood levels of methadone and subsequent risks of blood levelrelated adverse effects, including respiratory failure and torsades de pointes [38,62]. Induction of the metabolism of methadone poses the risk of inducing withdrawal reactions and increased levels of pain. Table 4 lists several methadone drug interactions identified in the literature that practitioners should be aware of and may need to take steps to alter the dosing of methadone to avoid problems. Additionally, due to genetic polymorphism identified with CYP2D6, CYP3A4 (both liver and intestinal), and other metabolizing enzymes, methadone shares with codeine and other agents the potential for variability in both metabolism and intestinal absorption [38]. The oral bioavailability of methadone tablets has been reported to average 70 80% for doses between 10 and 60 mg, with marked intersubject variation (range %) [38]. Intestinal CYP3A4 significantly contributes to the metabolism of methadone, with a predicted intestinal first-pass extraction around 20%, and thus significantly influences the oral availability of methadone. Debate in the literature regarding the mechanisms and clinical relevance of drug interactions with methadone have led some researchers to postulate that CYP450 enzymes other than CYP3A4 and CYP2D6 may play an important role in the overall metabolism of methadone [38,42,45,49,51,61]. Additionally, one study demonstrated that the various CYP450 enzymes most likely have different effects on the (R)- and (S)- enantiamers. For example, Wang and Devane in in vitro studies noted that CYP3A4 was the predominant enzyme involved in (R)-methadone metabolism, CYP2D6 was involved in both (R)- and (S)-methadone metabolism, and CYP2C8 played little role in the metabolism of (R)- methadone but had a similar, albeit small role in the metabolism of (S)-methadone [42]. This data may have implications for drug interactions that lead to substantial rise in serum levels of methadone due to situations in which inhibitors of different CYP450 enzymes are administered concurrently to patients receiving methadone. Table 4 Examples of clinically significant drug interactions with methadone [49,61] Interacting drug Mechanism Effect on methadone Amprenavir Induction of CYP3A4 Decreased plasma concentration Carbamazepine Induction of CYP3A4 Decreased plasma concentration Efavirenz Induction of CYP3A4 Decreased plasma concentration Erythromycin Inhibition of CYP3A4 Increased plasma concentration Fluconazole Inhibition of CYP3A4 Increased plasma concentration Fluoxetine Inhibition of CYP2D6 Increased plasma concentration Grapefruit juice Inhibition of CYP3A4 Increased plasma concentration Nelfinavir Induction of CYP3A4 Decreased plasma concentration Paroxetine Inhibition of CYP2D6 Increased plasma concentration Phenobarbital Induction of CYP3A4 Decreased plasma concentration Rifampin Induction of CYP3A4 Decreased plasma concentration Ritonavir Induction of CYP3A4 Decreased plasma concentration Sertraline Inhibition of CYP2D6 Increased plasma concentration

8 Effects of CYP450 on Opioid Agents Regardless of whether all of the metabolic pathways of methadone are fully understood, it is accepted that the CYP450 enzyme system plays an integral and important role in the metabolism of this drug. An important conclusion by Eap et al. [38] states, Methadone displays a large inter-individual variability in its pharmacokinetics and its pharmacodynamics, a variability which is both genetically and environmentally determined. It is thus of major importance that methadone treatment is individually adapted to each patient, in particular with regard to the dosage and to the choice of co-medications administered. Conclusion Selection of an appropriate opioid for a patient with pain involves many decisions. As illustrated in this review, the CYP450 enzyme system plays an important role in the metabolism of various opioids as well as a number of adjunctive medications that a pain patient may also be prescribed. Researchers have given us a broad understand of the CYP450 system including metabolism, drug interactions, and clinical significance of the interactions with specific opioids and other medications. As practitioners gain a working knowledge of the metabolism and pharmacokinetic interactions of opioids with other medications, they will be able to prescribe opioids with greater safety and allow patients to utilize their pain medications with perhaps one less risk affecting them. Disclosures The author has no disclosures to report. References 1 Chutka DS, Takahashi PY, Hoel RW. Inappropriate medications for elderly patients. Mayo Clin Proc 2004;79: Goldberg RM, Mabee J, Chan L, Wong S. Drugdrug and drug-disease interactions in the ED: Analysis of a high-risk population. Am J Emerg Med 1996;14: Levy RH, Thummel KE, Trager WF, Hansten PD, Eichelbaum M. Metabolic Drug Interactions. Philadelphia, PA: Lippincott Williams & Wilkins; Ciummo P, Natz NL. Interactions and drugmetabolizing enzymes. Am Pharm 1995;35: Guengerich FP. Cytochrome P450 and chemical toxicology. Chem Res Toxicol 2008;21: S27 6 Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions and adverse effects. Am Fam Physician 2007;76: Wilkerson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352: Slaughter RL, Edwards DJ. Recent advances: the cytochrome P450 enzymes. Ann Pharmacol 1995;29: Piscitelli SC, Rodvold KA. Drug Interactions in Infectious Diseases. Totowa, NJ: Humana Press; Murray M, Reidy GF. Selectivity in the inhibition of mammalian cytochrome P450 by chemical agents. Pharmacol Rev 1990;42: Dossing M, Pilsgaard H, Rasmussen B, Poulsen HE. Time course of phenobarbital and cimetidinemediated changes in hepatic drug metabolism. Eur J Clin Pharmacol 1983;25: Michalets EL, Update: Clinically significant cytochrome P450 drug interactions. Pharmacotherapy 1998;18: Johns-Cupp M, Tracy TS. Cytochrome P450: New nomenclature and clinical implications. Am Fam Physician 1998;57: Flockhart DA. Drug interactions: Cytochrome P450 drug interactions table. Indiana School of Medicine; Available at: iupui.edu/flockhart/table.htm (accessed December 15, 2008). 15 Somogyi AA, Barratt DT, Coller JT. Pharmacogenetics of opioids. Clin Pharmacol Ther 2007;81: Steiner E, Bertilsson L, Sawe J, Bertling I, Sjovist F. Polymorphic debrisoquin hydroxylation in 757 Swedish subjects. Clin Pharmacol Ther 1988;44: Relling MV, Cherrie J, Schell MJ, et al. Lower prevalence of the debrisoquin oxidative poor metabolizer phenotype in American black versus white subjects. Clin Pharmacol Ther 1991;50: Bertilsson L, Lou YQ, Du YL, et al. Pronounced differences between native Chinese and Swedish populations in the polymorphic hydroxylations of debrisoquin and S-mephenytoin. Clin Pharmacol Ther 1992;51: Sindrup SH, Brasen K, Bjerring P, et al. Codeine increases pain thresholds to copper vapor laser stimuli in extensive but not poor metabolizers of sparteine. Clin Pharmacol Ther 1990;48: Yue QY, Svensson JO, Alm C, Sjaqvist F, Sawe J. Codeine O-demethylation co-segregates with polymorphic debrisoquine hydroxylation. Br J Clin Pharmacol 1989;28: Chen ZR, Somogyi AA, Bochner F. Polymorphic O-demethylation of codeine. Lancet 1988;2:914 5.

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