Interethnic Differences in Genetic Polymorphisms of CYP2D6 in the U.S. Population: Clinical Implications
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《肿瘤学家》
LEARNING OBJECTIVES
After completing this course, the reader will be able to:
List the four different genotypes for CYP2D6 polymorphism.
Understand the potential effects of CYP2D6 polymorphism on the efficacy and safety for drugs metabolized via this enzyme.
List the ethnic groups that are most frequently affected by genetic variation of the CYP2D6 enzyme.
ABSTRACT
DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide interindividual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic variants of the CYP2D6 isozyme that result in varying levels of metabolic activity are of clinical importance in some settings. The exact nature of the clinical effect caused by polymorphisms of the gene depends on the drug in question and the specific variant alleles expressed, as individual variants result in differing phenotypes with a range of levels of enzymatic activity.
Compromised drug efficacy due to CYP2D6 variation has been documented with a variety of agents, and this review considers a number of examples, including the 5-HT3-receptor antagonists, which are used in oncology supportive care for the prophylaxis of nausea and vomiting. CYP2D6 is involved in the metabolism of all of the most commonly available agents, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism.
Significant interethnic differences in CYP2D6 allele frequencies have been demonstrated from studies across many countries. However, incidences of polymorphisms in the U.S. population have been challenging to characterize because of the country’s wide ethnic diversity. The CYP2D6 polymorphism may become more important as robust clinical tests become widely available and as the use of multiple medications and the attendant risk for drug–drug interactions increases.
INTRODUCTION
It is well recognized that the majority of drugs are metabolized via microsomal enzymes localized in the liver and, to a lesser extent, the small intestine [1]. The activity of many drugs depends on their interaction with enzymes of the cytochrome P450 (CYP) system. These enzymes, which are responsible for drug activation and metabolism, display wide interindividual variation that can lead to significant interindividual differences in drug clearance. Such metabolic differences can alter the dose–response relationship and can have a number of possible outcomes, ranging from therapeutic failure to a higher incidence of adverse events and toxicity [1, 2]. Genetic polymorphisms in drug-metabolizing enzymes are a major cause of variability in drug metabolism that leads to the occurrence of adverse effects or lack of therapeutic efficacy [1].
More than 50 human CYP isozymes have been identified to date [3]. Of these, more than 20 are encoded by genes that are functionally polymorphic, including CYP2A6, CYP2C9, CYP2C19, and CYP2D6. Consequently, approximately 40% of CYP-dependent drug metabolism is carried out by polymorphic enzymes [4].
CYP2D6 is the best characterized of these polymorphic CYP isozymes, with more than 75 allelic variants currently identified [3, 5]. These variants result from point mutations, deletions or additions, gene rearrangements, and deletion or duplication of the entire gene, and result in an increase, reduction, or complete loss of activity [3, 6, 7]. While it accounts for only 2%–5% of all hepatic CYP isozymes, CYP2D6 metabolizes approximately 25% of all clinically used medications, including some cytotoxics, tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals, Wilmington, DE), and many agents used to treat associated complications such as antiarrythmics, antiemetics, antidepressants, antipsychotics, and analgesics (Table 1) [6, 8]. Since the identification of the CYP2D6 polymorphism in the 1970s, several studies have shown that the frequencies of the alternative CYP2D6 phenotypes vary significantly among different ethnic groups [2, 3, 9] and that such polymorphisms may play a role in the induction of adverse effects from administration of some therapeutic agents [1]. Variation in CYP2D6 expression is also thought to increase the potential for drug–drug interactions, an important implication because of the increasing number of drugs being prescribed [10, 11]. For example, in the oncology setting, patients with advanced cancer receiving palliative therapy receive an average of five or more medications for symptom relief [11].
Cancer is the second leading cause of death in the U.S. (second only to cardiovascular disease). With the wide spectrum of drugs employed for treatment and supportive care that involve CYP2D6 in their metabolism, ethnic differences in activity of this enzyme, and the ethnically diverse population of the U.S., it is timely to review interethnic variation in the prevalence of CYP2D6 polymorphisms. This paper also discusses the clinical importance of this polymorphism in terms of therapeutic management, with a specific focus on the 5-HT3-receptor antagonists, which are widely used in oncology for the prophylaxis and treatment of chemotherapy-induced nausea and vomiting.
SIGNIFICANCE OF CYP2D6 POLYMORPHISMS
As stated previously, many commonly prescribed medications in the oncology arena are metabolized by CYP2D6 (Table 1), and polymorphisms of the CYP2D6 gene may potentially induce clinically important effects across a wide range of therapeutic areas. The nature of the effect caused by such polymorphisms depends on both the drug and variant alleles involved.
CYP2D6 polymorphisms can be classified according to one of four levels of activity: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs) [12]. The EM phenotype is expressed by the majority of the population and is therefore considered "the norm" (Fig. 1) [2, 13]. PMs inherit two deficient CYP2D6 alleles and, as a result, metabolize drugs at a notably slower rate. This leads to an accumulation of high levels of unmetabolized drugs that are CYP2D6 substrates, a concomitant greater potential for adverse events and drug–drug interactions, and lower efficacy for drugs requiring CYP2D6 activation (Table 2) [3]. The UM phenotype is caused by the duplication, multiduplication, or amplification of active CYP2D6 genes, including primarily the CYP2D6*2 allele, but also involving CYP2D6*1 and others [1, 11]. Individuals with the UM phenotype metabolize drugs at an ultrarapid rate, which may lead to a loss of therapeutic efficacy at standard doses [1, 11]. Individuals who are heterozygous for a defective CYP2D6 allele often demonstrate an IM phenotype [14]. This phenotype has a wide spectrum of metabolic activity that can range from marginally better than the PM phenotype to activity that is close to that of the EM phenotype.
Establishing which phenotype an individual has often depends on the administration of a probe drug that is a substrate for CYP2D6 (e.g., dextromethorphan, debrisoquine, or sparteine) and measuring the metabolite-to-parent ratio [3]. However, assigning an accurate phenotype may be complicated by the ability of certain drugs to inhibit CYP2D6 when coadministered with substrate drugs, because CYP2D6 is a low-capacity, high-affinity enzyme that is easily saturated by substrate. In such cases, metabolite formation of a probe drug may be reduced, potentially changing an individual’s apparent phenotype from an EM to a PM [15]. This phenomenon was demonstrated by Jeppesen et al. [16] in a study involving a group of healthy volunteers identified as CYP2D6 EMs. In that study, participants received single oral doses of four selective serotonin reuptake inhibitor (SSRI) antidepressants that were known to be CYP2D6 inhibitors: citalopram (Celexa®; Forest Pharmaceuticals, Inc., St. Louis), fluoxetine (Prozac®; Eli Lilly and Company, Indianapolis), fluvoxamine, and paroxetine (Paxil®; GlaxoSmithKline, Philadelphia). Three out of six volunteers given 40 or 80 mg of paroxetine changed to a PM phenotype, as determined by sparteine testing. The precise clinical frequency of this apparent transformation of phenotypes—termed phenocopying—depends on the study population, but is often not known [17].
INCIDENCE OF CYP2D6 PHENOTYPES
Studies conducted across many countries have demonstrated significant interethnic differences in CYP2D6 allele frequencies (Table 3), which may be important to consider when individualizing treatment. However, incidences of the various polymorphisms in the U.S. population have been challenging to characterize because of the large ethnic diversity that exists within the U.S. Non-Hispanic whites accounted for around 70% of the population in 2000, with the remaining 30% comprised of a wide range of races (Table 4) [18]. However, it has been estimated that the proportion of ethnic minorities in the U.S. population will increase to around 40% by 2020 [18], with the greatest increase seen among Hispanics [19]. The challenge is that individuals of European, African, and Hispanic ancestry have all emigrated from different regions that have different incidences of CYP2D6 polymorphisms. It may, therefore, be difficult to predict the likely prevalence of the UM phenotype accurately among African-Americans for example, as estimates of this phenotype in African populations vary from 4.9% in African-Americans [20] to 29% in Ethiopians [21], and data on what proportion of African-Americans is of Ethiopian descent are lacking. Wide ranges in the prevalence of both the UM and PM phenotypes have also been reported in individuals of European descent (0.8%–10% and 1.5%–10%, respectively) [22–25].
PM Phenotype
The frequency of the CYP2D6 PM phenotype varies across different populations. In general, whites have the highest frequency of the PM phenotype, with British and Swiss whites reported to have the greatest incidences (8.9% and 10%, respectively) [25, 26]. Conversely, the prevalence of PMs in Asian populations is relatively low, particularly among Thai, Chinese, and Japanese populations (0%–1.2%) [27–29]. The prevalence of the PM phenotype is slightly higher among Asians in the Indian subcontinent than in the Asian populations of southeastern and eastern Asia, with frequencies of 1.8%–4.8% reported [30–33].
The low frequency of PMs among Asians compared with whites can be explained by an unequal distribution of CYP2D6 gene alleles among different populations. In particular, the PM phenotype in whites is primarily a result of the presence of the defective alleles CYP2D6*3 and CYP2D6*4. These alleles are rarely found in Chinese people, which accounts for the low frequency of PMs in that population [34]. However, the allele CYP2D6*10 plays an important role in drug metabolism in Asian populations. This mutation has a lower substrate affinity, resulting in a shift in the drug reaction curve and, therefore, lower activity [8]. CYP2D6*10 may be present in as much as 50% of Asians and is responsible for diminished enzyme activity in IMs [9, 34].
Reports on the prevalence of PMs in African populations differ widely, with estimates varying in the range of 0%–19% [21, 35–38]. There is also a wide range in the incidence of PMs reported in African-Americans, 1.9%–7.3% [39–42]. Studies suggest that a mutant allele, similar to the CYP2D6*10 allele present in many Asians, is associated with lower metabolic rates and may occur in high frequencies in populations of African descent [43, 44]. This allele, identified as CYP2D6*17, may play a role in the variation in CYP2D6 phenotypes seen among Black populations, although other variant alleles may also be involved.
Pharmacogenetic data from Hispanic populations are of particular relevance in evaluating CYP2D6 phenotypes, as the Hispanic population is a growing sector of the population, especially in the U.S. Although few studies have investigated the prevalence of CYP2D6 phenotypes in Hispanics, the prevalence of PMs is reported to be 2.2%–6.6% [45–48]. These studies, reflecting both Amerindian populations and selected Hispanic populations, demonstrate variability by region but generally show the CYP 2D6*4 alleleic frequency to be low in Amerindian populations, but not as low as in Chinese populations. In the Hispanic populations tested, the frequency is more similar to those of European populations, including data from Spain. The frequencies of other genetic variations in the Hispanic populations that have been studied are also more similar to frequencies seen in Europe. Overall interethnic differences in the distribution of CYP2D6 alleles and activity are now well understood. The incidence of the PM phenotype appears to be higher among Caucasians, possibly as a result of founder effects or population drift. This phenotype is less frequent in African and Asian populations. In contrast (as discussed below), the UM phenotype is most common in eastern Africa and appears to have traced a migratory path into Spanish populations, but not to have extended significantly further. This phenotype is relatively rare in Caucasians and among West Africans and Asians.
UM Phenotype
The clinical consequence of the CYP2D6 UM phenotype may be as significant as the PM phenotype in terms of therapeutic implications, yet few studies have investigated the incidence of UMs. Available reports, however, suggest that the frequency of UMs varies among ethnic groups, with studies reporting low prevalence in some European white populations (0.8% in Denmark and Germany, 1.0% in Sweden) [22, 49, 50] and a much higher prevalence in populations from countries surrounding the Mediterranean Sea (8.7% in Turkey and 10% in Spain) [23, 24]. The highest frequencies of the UM phenotype are reported in Ethiopians (29%) [21] and Saudi Arabians (21%) [51]. The prevalence rates of the UM phenotype in American Caucasians and Blacks are reported to be 4.3% and 4.9%, respectively [20].
CLINICAL IMPACT OF THE CYP2D6 POLYMORPHISM ON DRUG EFFECT
As mentioned earlier, CYP2D6 is responsible for the metabolism of approximately one quarter of all drugs. Consequently, polymorphisms of the gene have the potential to affect efficacy, drug–drug interactions, and adverse events. Indeed, clinical effects of CYP2D6 polymorphisms have been reported for a number of drug classes, including many classes used for oncology supportive care, such as the anti-depressant desipramine (Norpramin®; Aventis Pharmaceuticals Inc., Bridgewater, NJ) and fluoxetine [52, 53], analgesics, neuroleptics, and 5-HT3-receptor antagonists. Clinical consequences are particularly serious when using tricyclic antidepressants (TCAs), most of which are metabolized by CYP2D6, as these agents are toxic at high plasma concentrations and may lead to unpleasant side effects or life-threatening cardiac complications [54]. The TCAs may be used in oncology in a number of supportive care settings, including as adjuvant medication for difficult-to-manage pain in addition to cancer-related depression.
A higher incidence of adverse events has also been reported in PMs that receive neuroleptics, which patients with cancer may receive for delirium [55, 56]. These adverse effects include pseudoparkinsonism, with ratings for the disorder found to be significantly higher in PM psychiatric inpatients treated with haloperidol than normal metabolizers (p = .02) [57]. Parkinsonism and tardive dys-kinesia during zuclopenthixol-decanoate treatment were also shown to be more common in at least one patient with a mutated CYP2D6 allele (odds ratio, 2.3 and 1.7, respectively) [56]. Overall, the slower metabolism of PMs may have a cascade effect when multiple concomitant medications that are metabolized via CYP2D6 are administered, increasing the potential for adverse side effects. For example, products metabolized by CYP2D6 that are known to cause QTc elongation could potentially lead to greater patient risk resulting from prolonged drug exposure. The 5-HT3-receptor antagonists dolasetron (Anzemet®; Aventis Pharmaceuticals Inc.), palonosetron (Aloxi®; MGI Pharma, Inc., Bloomington, MN), and tropisetron (not available in the U.S.) all contain warnings for the risk of arrhythmias in their labeling. This risk may increase when these antiemetics are coadministered with other agents that have the ability to cause cardiac conduction defects, especially when administered to PM patients.
As noted previously, slow drug metabolism by PMs may also impact efficacy in cases in which the drug requires metabolizing to an active metabolite. This is a concern for cancer patients being given pain relief, with a lower analgesic effect of codeine seen in PMs, as conversion of the drug to morphine is CYP2D6-dependent [58,59]. This could also be an issue for the antiemetic dolasetron, as CYP2D6 is also required for its conversion to the active metabolite hydro-dolasetron. Phenocopying can also occur when a CYP2D6 inhibitor is administered concurrently with an agent that is metabolized to its active form by the CYP2D6 isozyme. For example, coadministration of the antiarrhythmic quinidine with codeine to an EM individual can result in the loss of the analgesic effect of codeine because of the inhibition of CYP2D6 by quinidine [15]. Conversely, codeine given to UMs can result in excessive formation of morphine, leading to side effects such as abdominal pain [60].
The UM phenotype has been less well characterized than the PM phenotype, though it may have significant clinical consequences, particularly in the selection of an appropriate drug dosage. This is exemplified by the TCA nor-tryptyline (Pamelor®; Mallinckrodt Inc., St. Louis), which is effective in PMs at doses as low as 10–20 mg, but which requires doses up to 500 mg in UMs [61]. Thus, administration of standard doses of CYP2D6-metabolized drugs to UM individuals may result in therapeutic failure because of a low plasma concentration of active drug [14], or conversely, may lead to supratherapeutic levels of active metabolite formation and potentially serious side effects [60].
5-HT3-Receptor Antagonists
The 5-HT3-receptor antagonists—granisetron (Kytril®, Hoffmann-La Roche Inc., Nutley, NJ), ondansetron (Zofran®; GlaxoSmithKline), dolasetron, tropisetron, and the recently introduced palonosetron—are highly effective antiemetics, widely used for the prophylaxis and treatment of nausea and vomiting induced by chemotherapy and radiotherapy. Despite the widespread use of these agents, however, it is well recognized that around 20%–30% of patients do not respond satisfactorily [62]. Furthermore, nausea and vomiting remain two of the biggest concerns for patients receiving cytotoxic treatment and, if incompletely controlled, can reduce the patient’s quality of life and lead to further complications such as dehydration and even patients delaying or refusing future therapy. It has recently been suggested that CYP2D6 polymorphisms may account, at least in part, for the variability in interpatient responses to some of the 5-HT3-receptor antagonists [63]. CYP2D6 plays a role in the metabolism of four of the commonly used 5-HT3-receptor antagonists—tropisetron, ondansetron, dolasetron, and palonosetron [64]. Tropisetron is metabolized almost entirely by the CYP2D6 isozyme; ondansetron, dolasetron, and palonosetron are metabolized by other CYP isozymes in addition to CYP2D6. Granisetron is the only 5-HT3-receptor antagonist that does not involve CYP2D6 in its metabolism and is instead metabolized by members of the CYP3A subfamily [65].
The antiemetic efficacy and serum concentrations of the 5-HT3-receptor antagonists ondansetron and tropisetron were shown, in a recent study, to be affected by CYP2D6 phenotype [63]. The study included 270 patients receiving moderately or highly emetogenic chemotherapy—96 received tropisetron (5 mg once a day) and 174 received ondansetron (8 mg twice a day). Genetically defined UMs were found to have a significantly higher frequency of vomiting in the first 4 hours (p < .001) and 5–24 hours (p < .03) after chemotherapy than all other patients (Fig. 2) [63]. With tropisetron relying almost exclusively on CYP2D6 for its metabolism, the gene–dose effect was more apparent with this antiemetic than with ondansetron [63]. Compromised antiemetic efficacy with ondansetron in UM patients has also been very recently demonstrated in a postoperative setting [66]. Following prophylactic treatment with 4 mg of ondansetron, genetically defined UMs (patients with three copies of the CYP2D6 gene) experienced significantly higher incidences of postoperative vomiting than PMs, IMs, or EMs (5 of 11 patients, 45%; p < .01). Genetic variation has also been suggested as a potential explanation for the finding that patients refractory to treatment with ondansetron experience emetic protection with granisetron [67, 68]. Conversely, PM patients receiving 5-HT3-receptor antagonists metabolized by CYP2D6 are likely to have higher serum concentrations of these agents [63], which may prolong the duration of drug effect, but may also increase the duration of drug-induced adverse events and increase the potential for drug–drug interactions. Adverse effects experienced by PM patients may be exacerbated with the administration of multiple medications, as illustrated in the following example with tamoxifen.
Tamoxifen
The selective estrogen receptor modulator (SERM) tamoxifen has been used for many years as endocrine treatment for hormone receptor–positive breast cancer, with indications in the metastatic, adjuvant, and preventative settings. The minimal acute toxicity of endocrine treatments such as tamoxifen compared with chemotherapy helps maintain patients’ quality of life, and increasing emphasis is being placed on these treatments to delay the use of cytotoxic therapies for as long as possible.
Tamoxifen’s adverse-event profile includes venous thrombosis, endometrial cancer, and, most commonly, hot flashes, which are often treated with an SSRI antidepressant. Tamoxifen is extensively hepatically metabolized to several primary and secondary metabolites by multiple CYP enzymes, including CYP2D6. With some SSRIs (e.g., paroxetine) known to inhibit CYP2D6, a study was recently conducted to investigate the effects of SSRI coadministration on plasma concentrations of tamoxifen and its metabolites in addition to the effects of individual patient genotypes [69]. A strong association was shown between CYP2D6 activity and plasma levels of the active tamoxifen metabolite, endoxifen. Concomitant use of paroxetine was associated with lower endoxifen plasma concentrations, with the magnitude of this difference being dependent on CYP2D6 genotype. It is possible, therefore, that patients taking some SSRIs may be less responsive to tamoxifen because of a lower rate of formation of its active metabolite, which may be exacerbated in individuals with slowed CYP2D6 metabolism. The possibility that tamoxifen’s antitumoral activity could be affected in this way needs further testing in clinical trials designed to record clinical outcome in conjunction with genotype and coadministered medication with the potential to affect CYP2D6.
CONCLUSIONS
It is clear that drugs that are substrates for CYP2D6 can display wide interindividual variation in their metabolism as a result of polymorphisms in the CYP2D6 gene. Variation in CYP2D6 activity has important therapeutic consequences and can play a significant role in the development of adverse events or therapeutic failure in susceptible individuals. CYP2D6 polymorphisms are likely to become increasingly important in the coming years as an increasing number of patients are prescribed multiple medications, a proportion of which are likely to be metabolized by this isozyme. Multiple prescription and over-the-counter drug use is particularly common in the U.S., a country in which genotype incidence rates are not intuitively obvious and in which a high rate of serious and fatal adverse drug reactions occurs [70]. Furthermore, a study conducted in a psychiatric setting in the U.S. has shown that CYP2D6 polymorphisms can have a marked effect on the cost of treating a patient; UM and PM patients were found to cost between $4,000 and $6,000 per year more to treat than EM or IM individuals [71]. Thus, genotyping for individuals receiving single or multiple drugs that are metabolized by CYP2D6 may help clinicians to avoid adverse drug–drug interactions and to individualize treatment with medications better. The availability of a number of robust U.S. Food and Drug Administration–approved tests for genetic variants of CYP2D6 will likely increase the frequency of testing, although screening for polymorphisms in drug-metabolizing enzymes is cost-prohibitive in some settings and is not yet widely recommended [72].
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The authors indicate no potential conflicts of interest.
ACKNOWLEDGMENT
The writing of this paper was supported by Hoffmann-La Roche, by a Pharmacogenetics Research Network Grant, the NIGMS (U-01- GM61373), and by a Clinical Pharmacology Training Grant (T32 GM 56898), Bethesda, MD.
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After completing this course, the reader will be able to:
List the four different genotypes for CYP2D6 polymorphism.
Understand the potential effects of CYP2D6 polymorphism on the efficacy and safety for drugs metabolized via this enzyme.
List the ethnic groups that are most frequently affected by genetic variation of the CYP2D6 enzyme.
ABSTRACT
DNA polymorphisms have been identified in the genes encoding a number of the cytochrome P450 (CYP) enzymes, leading to wide interindividual variation in drug clearance. CYP2D6 metabolizes a significant number of clinically used medications, and genetic variants of the CYP2D6 isozyme that result in varying levels of metabolic activity are of clinical importance in some settings. The exact nature of the clinical effect caused by polymorphisms of the gene depends on the drug in question and the specific variant alleles expressed, as individual variants result in differing phenotypes with a range of levels of enzymatic activity.
Compromised drug efficacy due to CYP2D6 variation has been documented with a variety of agents, and this review considers a number of examples, including the 5-HT3-receptor antagonists, which are used in oncology supportive care for the prophylaxis of nausea and vomiting. CYP2D6 is involved in the metabolism of all of the most commonly available agents, except granisetron, and their efficacy and side effects may therefore be affected by the CYP2D6 polymorphism.
Significant interethnic differences in CYP2D6 allele frequencies have been demonstrated from studies across many countries. However, incidences of polymorphisms in the U.S. population have been challenging to characterize because of the country’s wide ethnic diversity. The CYP2D6 polymorphism may become more important as robust clinical tests become widely available and as the use of multiple medications and the attendant risk for drug–drug interactions increases.
INTRODUCTION
It is well recognized that the majority of drugs are metabolized via microsomal enzymes localized in the liver and, to a lesser extent, the small intestine [1]. The activity of many drugs depends on their interaction with enzymes of the cytochrome P450 (CYP) system. These enzymes, which are responsible for drug activation and metabolism, display wide interindividual variation that can lead to significant interindividual differences in drug clearance. Such metabolic differences can alter the dose–response relationship and can have a number of possible outcomes, ranging from therapeutic failure to a higher incidence of adverse events and toxicity [1, 2]. Genetic polymorphisms in drug-metabolizing enzymes are a major cause of variability in drug metabolism that leads to the occurrence of adverse effects or lack of therapeutic efficacy [1].
More than 50 human CYP isozymes have been identified to date [3]. Of these, more than 20 are encoded by genes that are functionally polymorphic, including CYP2A6, CYP2C9, CYP2C19, and CYP2D6. Consequently, approximately 40% of CYP-dependent drug metabolism is carried out by polymorphic enzymes [4].
CYP2D6 is the best characterized of these polymorphic CYP isozymes, with more than 75 allelic variants currently identified [3, 5]. These variants result from point mutations, deletions or additions, gene rearrangements, and deletion or duplication of the entire gene, and result in an increase, reduction, or complete loss of activity [3, 6, 7]. While it accounts for only 2%–5% of all hepatic CYP isozymes, CYP2D6 metabolizes approximately 25% of all clinically used medications, including some cytotoxics, tamoxifen (Nolvadex®; AstraZeneca Pharmaceuticals, Wilmington, DE), and many agents used to treat associated complications such as antiarrythmics, antiemetics, antidepressants, antipsychotics, and analgesics (Table 1) [6, 8]. Since the identification of the CYP2D6 polymorphism in the 1970s, several studies have shown that the frequencies of the alternative CYP2D6 phenotypes vary significantly among different ethnic groups [2, 3, 9] and that such polymorphisms may play a role in the induction of adverse effects from administration of some therapeutic agents [1]. Variation in CYP2D6 expression is also thought to increase the potential for drug–drug interactions, an important implication because of the increasing number of drugs being prescribed [10, 11]. For example, in the oncology setting, patients with advanced cancer receiving palliative therapy receive an average of five or more medications for symptom relief [11].
Cancer is the second leading cause of death in the U.S. (second only to cardiovascular disease). With the wide spectrum of drugs employed for treatment and supportive care that involve CYP2D6 in their metabolism, ethnic differences in activity of this enzyme, and the ethnically diverse population of the U.S., it is timely to review interethnic variation in the prevalence of CYP2D6 polymorphisms. This paper also discusses the clinical importance of this polymorphism in terms of therapeutic management, with a specific focus on the 5-HT3-receptor antagonists, which are widely used in oncology for the prophylaxis and treatment of chemotherapy-induced nausea and vomiting.
SIGNIFICANCE OF CYP2D6 POLYMORPHISMS
As stated previously, many commonly prescribed medications in the oncology arena are metabolized by CYP2D6 (Table 1), and polymorphisms of the CYP2D6 gene may potentially induce clinically important effects across a wide range of therapeutic areas. The nature of the effect caused by such polymorphisms depends on both the drug and variant alleles involved.
CYP2D6 polymorphisms can be classified according to one of four levels of activity: poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs) [12]. The EM phenotype is expressed by the majority of the population and is therefore considered "the norm" (Fig. 1) [2, 13]. PMs inherit two deficient CYP2D6 alleles and, as a result, metabolize drugs at a notably slower rate. This leads to an accumulation of high levels of unmetabolized drugs that are CYP2D6 substrates, a concomitant greater potential for adverse events and drug–drug interactions, and lower efficacy for drugs requiring CYP2D6 activation (Table 2) [3]. The UM phenotype is caused by the duplication, multiduplication, or amplification of active CYP2D6 genes, including primarily the CYP2D6*2 allele, but also involving CYP2D6*1 and others [1, 11]. Individuals with the UM phenotype metabolize drugs at an ultrarapid rate, which may lead to a loss of therapeutic efficacy at standard doses [1, 11]. Individuals who are heterozygous for a defective CYP2D6 allele often demonstrate an IM phenotype [14]. This phenotype has a wide spectrum of metabolic activity that can range from marginally better than the PM phenotype to activity that is close to that of the EM phenotype.
Establishing which phenotype an individual has often depends on the administration of a probe drug that is a substrate for CYP2D6 (e.g., dextromethorphan, debrisoquine, or sparteine) and measuring the metabolite-to-parent ratio [3]. However, assigning an accurate phenotype may be complicated by the ability of certain drugs to inhibit CYP2D6 when coadministered with substrate drugs, because CYP2D6 is a low-capacity, high-affinity enzyme that is easily saturated by substrate. In such cases, metabolite formation of a probe drug may be reduced, potentially changing an individual’s apparent phenotype from an EM to a PM [15]. This phenomenon was demonstrated by Jeppesen et al. [16] in a study involving a group of healthy volunteers identified as CYP2D6 EMs. In that study, participants received single oral doses of four selective serotonin reuptake inhibitor (SSRI) antidepressants that were known to be CYP2D6 inhibitors: citalopram (Celexa®; Forest Pharmaceuticals, Inc., St. Louis), fluoxetine (Prozac®; Eli Lilly and Company, Indianapolis), fluvoxamine, and paroxetine (Paxil®; GlaxoSmithKline, Philadelphia). Three out of six volunteers given 40 or 80 mg of paroxetine changed to a PM phenotype, as determined by sparteine testing. The precise clinical frequency of this apparent transformation of phenotypes—termed phenocopying—depends on the study population, but is often not known [17].
INCIDENCE OF CYP2D6 PHENOTYPES
Studies conducted across many countries have demonstrated significant interethnic differences in CYP2D6 allele frequencies (Table 3), which may be important to consider when individualizing treatment. However, incidences of the various polymorphisms in the U.S. population have been challenging to characterize because of the large ethnic diversity that exists within the U.S. Non-Hispanic whites accounted for around 70% of the population in 2000, with the remaining 30% comprised of a wide range of races (Table 4) [18]. However, it has been estimated that the proportion of ethnic minorities in the U.S. population will increase to around 40% by 2020 [18], with the greatest increase seen among Hispanics [19]. The challenge is that individuals of European, African, and Hispanic ancestry have all emigrated from different regions that have different incidences of CYP2D6 polymorphisms. It may, therefore, be difficult to predict the likely prevalence of the UM phenotype accurately among African-Americans for example, as estimates of this phenotype in African populations vary from 4.9% in African-Americans [20] to 29% in Ethiopians [21], and data on what proportion of African-Americans is of Ethiopian descent are lacking. Wide ranges in the prevalence of both the UM and PM phenotypes have also been reported in individuals of European descent (0.8%–10% and 1.5%–10%, respectively) [22–25].
PM Phenotype
The frequency of the CYP2D6 PM phenotype varies across different populations. In general, whites have the highest frequency of the PM phenotype, with British and Swiss whites reported to have the greatest incidences (8.9% and 10%, respectively) [25, 26]. Conversely, the prevalence of PMs in Asian populations is relatively low, particularly among Thai, Chinese, and Japanese populations (0%–1.2%) [27–29]. The prevalence of the PM phenotype is slightly higher among Asians in the Indian subcontinent than in the Asian populations of southeastern and eastern Asia, with frequencies of 1.8%–4.8% reported [30–33].
The low frequency of PMs among Asians compared with whites can be explained by an unequal distribution of CYP2D6 gene alleles among different populations. In particular, the PM phenotype in whites is primarily a result of the presence of the defective alleles CYP2D6*3 and CYP2D6*4. These alleles are rarely found in Chinese people, which accounts for the low frequency of PMs in that population [34]. However, the allele CYP2D6*10 plays an important role in drug metabolism in Asian populations. This mutation has a lower substrate affinity, resulting in a shift in the drug reaction curve and, therefore, lower activity [8]. CYP2D6*10 may be present in as much as 50% of Asians and is responsible for diminished enzyme activity in IMs [9, 34].
Reports on the prevalence of PMs in African populations differ widely, with estimates varying in the range of 0%–19% [21, 35–38]. There is also a wide range in the incidence of PMs reported in African-Americans, 1.9%–7.3% [39–42]. Studies suggest that a mutant allele, similar to the CYP2D6*10 allele present in many Asians, is associated with lower metabolic rates and may occur in high frequencies in populations of African descent [43, 44]. This allele, identified as CYP2D6*17, may play a role in the variation in CYP2D6 phenotypes seen among Black populations, although other variant alleles may also be involved.
Pharmacogenetic data from Hispanic populations are of particular relevance in evaluating CYP2D6 phenotypes, as the Hispanic population is a growing sector of the population, especially in the U.S. Although few studies have investigated the prevalence of CYP2D6 phenotypes in Hispanics, the prevalence of PMs is reported to be 2.2%–6.6% [45–48]. These studies, reflecting both Amerindian populations and selected Hispanic populations, demonstrate variability by region but generally show the CYP 2D6*4 alleleic frequency to be low in Amerindian populations, but not as low as in Chinese populations. In the Hispanic populations tested, the frequency is more similar to those of European populations, including data from Spain. The frequencies of other genetic variations in the Hispanic populations that have been studied are also more similar to frequencies seen in Europe. Overall interethnic differences in the distribution of CYP2D6 alleles and activity are now well understood. The incidence of the PM phenotype appears to be higher among Caucasians, possibly as a result of founder effects or population drift. This phenotype is less frequent in African and Asian populations. In contrast (as discussed below), the UM phenotype is most common in eastern Africa and appears to have traced a migratory path into Spanish populations, but not to have extended significantly further. This phenotype is relatively rare in Caucasians and among West Africans and Asians.
UM Phenotype
The clinical consequence of the CYP2D6 UM phenotype may be as significant as the PM phenotype in terms of therapeutic implications, yet few studies have investigated the incidence of UMs. Available reports, however, suggest that the frequency of UMs varies among ethnic groups, with studies reporting low prevalence in some European white populations (0.8% in Denmark and Germany, 1.0% in Sweden) [22, 49, 50] and a much higher prevalence in populations from countries surrounding the Mediterranean Sea (8.7% in Turkey and 10% in Spain) [23, 24]. The highest frequencies of the UM phenotype are reported in Ethiopians (29%) [21] and Saudi Arabians (21%) [51]. The prevalence rates of the UM phenotype in American Caucasians and Blacks are reported to be 4.3% and 4.9%, respectively [20].
CLINICAL IMPACT OF THE CYP2D6 POLYMORPHISM ON DRUG EFFECT
As mentioned earlier, CYP2D6 is responsible for the metabolism of approximately one quarter of all drugs. Consequently, polymorphisms of the gene have the potential to affect efficacy, drug–drug interactions, and adverse events. Indeed, clinical effects of CYP2D6 polymorphisms have been reported for a number of drug classes, including many classes used for oncology supportive care, such as the anti-depressant desipramine (Norpramin®; Aventis Pharmaceuticals Inc., Bridgewater, NJ) and fluoxetine [52, 53], analgesics, neuroleptics, and 5-HT3-receptor antagonists. Clinical consequences are particularly serious when using tricyclic antidepressants (TCAs), most of which are metabolized by CYP2D6, as these agents are toxic at high plasma concentrations and may lead to unpleasant side effects or life-threatening cardiac complications [54]. The TCAs may be used in oncology in a number of supportive care settings, including as adjuvant medication for difficult-to-manage pain in addition to cancer-related depression.
A higher incidence of adverse events has also been reported in PMs that receive neuroleptics, which patients with cancer may receive for delirium [55, 56]. These adverse effects include pseudoparkinsonism, with ratings for the disorder found to be significantly higher in PM psychiatric inpatients treated with haloperidol than normal metabolizers (p = .02) [57]. Parkinsonism and tardive dys-kinesia during zuclopenthixol-decanoate treatment were also shown to be more common in at least one patient with a mutated CYP2D6 allele (odds ratio, 2.3 and 1.7, respectively) [56]. Overall, the slower metabolism of PMs may have a cascade effect when multiple concomitant medications that are metabolized via CYP2D6 are administered, increasing the potential for adverse side effects. For example, products metabolized by CYP2D6 that are known to cause QTc elongation could potentially lead to greater patient risk resulting from prolonged drug exposure. The 5-HT3-receptor antagonists dolasetron (Anzemet®; Aventis Pharmaceuticals Inc.), palonosetron (Aloxi®; MGI Pharma, Inc., Bloomington, MN), and tropisetron (not available in the U.S.) all contain warnings for the risk of arrhythmias in their labeling. This risk may increase when these antiemetics are coadministered with other agents that have the ability to cause cardiac conduction defects, especially when administered to PM patients.
As noted previously, slow drug metabolism by PMs may also impact efficacy in cases in which the drug requires metabolizing to an active metabolite. This is a concern for cancer patients being given pain relief, with a lower analgesic effect of codeine seen in PMs, as conversion of the drug to morphine is CYP2D6-dependent [58,59]. This could also be an issue for the antiemetic dolasetron, as CYP2D6 is also required for its conversion to the active metabolite hydro-dolasetron. Phenocopying can also occur when a CYP2D6 inhibitor is administered concurrently with an agent that is metabolized to its active form by the CYP2D6 isozyme. For example, coadministration of the antiarrhythmic quinidine with codeine to an EM individual can result in the loss of the analgesic effect of codeine because of the inhibition of CYP2D6 by quinidine [15]. Conversely, codeine given to UMs can result in excessive formation of morphine, leading to side effects such as abdominal pain [60].
The UM phenotype has been less well characterized than the PM phenotype, though it may have significant clinical consequences, particularly in the selection of an appropriate drug dosage. This is exemplified by the TCA nor-tryptyline (Pamelor®; Mallinckrodt Inc., St. Louis), which is effective in PMs at doses as low as 10–20 mg, but which requires doses up to 500 mg in UMs [61]. Thus, administration of standard doses of CYP2D6-metabolized drugs to UM individuals may result in therapeutic failure because of a low plasma concentration of active drug [14], or conversely, may lead to supratherapeutic levels of active metabolite formation and potentially serious side effects [60].
5-HT3-Receptor Antagonists
The 5-HT3-receptor antagonists—granisetron (Kytril®, Hoffmann-La Roche Inc., Nutley, NJ), ondansetron (Zofran®; GlaxoSmithKline), dolasetron, tropisetron, and the recently introduced palonosetron—are highly effective antiemetics, widely used for the prophylaxis and treatment of nausea and vomiting induced by chemotherapy and radiotherapy. Despite the widespread use of these agents, however, it is well recognized that around 20%–30% of patients do not respond satisfactorily [62]. Furthermore, nausea and vomiting remain two of the biggest concerns for patients receiving cytotoxic treatment and, if incompletely controlled, can reduce the patient’s quality of life and lead to further complications such as dehydration and even patients delaying or refusing future therapy. It has recently been suggested that CYP2D6 polymorphisms may account, at least in part, for the variability in interpatient responses to some of the 5-HT3-receptor antagonists [63]. CYP2D6 plays a role in the metabolism of four of the commonly used 5-HT3-receptor antagonists—tropisetron, ondansetron, dolasetron, and palonosetron [64]. Tropisetron is metabolized almost entirely by the CYP2D6 isozyme; ondansetron, dolasetron, and palonosetron are metabolized by other CYP isozymes in addition to CYP2D6. Granisetron is the only 5-HT3-receptor antagonist that does not involve CYP2D6 in its metabolism and is instead metabolized by members of the CYP3A subfamily [65].
The antiemetic efficacy and serum concentrations of the 5-HT3-receptor antagonists ondansetron and tropisetron were shown, in a recent study, to be affected by CYP2D6 phenotype [63]. The study included 270 patients receiving moderately or highly emetogenic chemotherapy—96 received tropisetron (5 mg once a day) and 174 received ondansetron (8 mg twice a day). Genetically defined UMs were found to have a significantly higher frequency of vomiting in the first 4 hours (p < .001) and 5–24 hours (p < .03) after chemotherapy than all other patients (Fig. 2) [63]. With tropisetron relying almost exclusively on CYP2D6 for its metabolism, the gene–dose effect was more apparent with this antiemetic than with ondansetron [63]. Compromised antiemetic efficacy with ondansetron in UM patients has also been very recently demonstrated in a postoperative setting [66]. Following prophylactic treatment with 4 mg of ondansetron, genetically defined UMs (patients with three copies of the CYP2D6 gene) experienced significantly higher incidences of postoperative vomiting than PMs, IMs, or EMs (5 of 11 patients, 45%; p < .01). Genetic variation has also been suggested as a potential explanation for the finding that patients refractory to treatment with ondansetron experience emetic protection with granisetron [67, 68]. Conversely, PM patients receiving 5-HT3-receptor antagonists metabolized by CYP2D6 are likely to have higher serum concentrations of these agents [63], which may prolong the duration of drug effect, but may also increase the duration of drug-induced adverse events and increase the potential for drug–drug interactions. Adverse effects experienced by PM patients may be exacerbated with the administration of multiple medications, as illustrated in the following example with tamoxifen.
Tamoxifen
The selective estrogen receptor modulator (SERM) tamoxifen has been used for many years as endocrine treatment for hormone receptor–positive breast cancer, with indications in the metastatic, adjuvant, and preventative settings. The minimal acute toxicity of endocrine treatments such as tamoxifen compared with chemotherapy helps maintain patients’ quality of life, and increasing emphasis is being placed on these treatments to delay the use of cytotoxic therapies for as long as possible.
Tamoxifen’s adverse-event profile includes venous thrombosis, endometrial cancer, and, most commonly, hot flashes, which are often treated with an SSRI antidepressant. Tamoxifen is extensively hepatically metabolized to several primary and secondary metabolites by multiple CYP enzymes, including CYP2D6. With some SSRIs (e.g., paroxetine) known to inhibit CYP2D6, a study was recently conducted to investigate the effects of SSRI coadministration on plasma concentrations of tamoxifen and its metabolites in addition to the effects of individual patient genotypes [69]. A strong association was shown between CYP2D6 activity and plasma levels of the active tamoxifen metabolite, endoxifen. Concomitant use of paroxetine was associated with lower endoxifen plasma concentrations, with the magnitude of this difference being dependent on CYP2D6 genotype. It is possible, therefore, that patients taking some SSRIs may be less responsive to tamoxifen because of a lower rate of formation of its active metabolite, which may be exacerbated in individuals with slowed CYP2D6 metabolism. The possibility that tamoxifen’s antitumoral activity could be affected in this way needs further testing in clinical trials designed to record clinical outcome in conjunction with genotype and coadministered medication with the potential to affect CYP2D6.
CONCLUSIONS
It is clear that drugs that are substrates for CYP2D6 can display wide interindividual variation in their metabolism as a result of polymorphisms in the CYP2D6 gene. Variation in CYP2D6 activity has important therapeutic consequences and can play a significant role in the development of adverse events or therapeutic failure in susceptible individuals. CYP2D6 polymorphisms are likely to become increasingly important in the coming years as an increasing number of patients are prescribed multiple medications, a proportion of which are likely to be metabolized by this isozyme. Multiple prescription and over-the-counter drug use is particularly common in the U.S., a country in which genotype incidence rates are not intuitively obvious and in which a high rate of serious and fatal adverse drug reactions occurs [70]. Furthermore, a study conducted in a psychiatric setting in the U.S. has shown that CYP2D6 polymorphisms can have a marked effect on the cost of treating a patient; UM and PM patients were found to cost between $4,000 and $6,000 per year more to treat than EM or IM individuals [71]. Thus, genotyping for individuals receiving single or multiple drugs that are metabolized by CYP2D6 may help clinicians to avoid adverse drug–drug interactions and to individualize treatment with medications better. The availability of a number of robust U.S. Food and Drug Administration–approved tests for genetic variants of CYP2D6 will likely increase the frequency of testing, although screening for polymorphisms in drug-metabolizing enzymes is cost-prohibitive in some settings and is not yet widely recommended [72].
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST
The authors indicate no potential conflicts of interest.
ACKNOWLEDGMENT
The writing of this paper was supported by Hoffmann-La Roche, by a Pharmacogenetics Research Network Grant, the NIGMS (U-01- GM61373), and by a Clinical Pharmacology Training Grant (T32 GM 56898), Bethesda, MD.
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