TY - JOUR
AU - Son, In, Ja
AB - Abstract Purpose. A decision matrix for identifying drugs for which pharmacogenetic drug monitoring (PDM) provides the greatest benefit in a Korean setting is described. Summary. We developed a decision matrix including the ethnic frequency of clinically relevant polymorphic cytochrome P-450 (CYP) enzymes, and the metabolic profiles and adverse drug reactions of drugs. Using the developed decision matrix based on the population allele frequencies of CYP enzymes, we identified potential candidates for PDM among the most commonly used drugs at Seoul National University Hospital (SNUH). Collectively, 17 of these drugs were largely metabolized by at least one polymorphic CYP enzyme. Pharmacogenetic information was used to identify CYP2C9, CYP2C19, and CYP2D6 as the major CYP enzymes of clinical importance for pharmacologic effect and safety in Koreans. The frequencies of poor and intermediate metabolizers among Koreans were 0% and 2.3–12% for CYP2C9, 12% and 42% for CYP2C19, and 0.44% and 28% for CYP2D6, respectively. The frequency of ultrarapid metabolizers of CYP2D6 was 2.28%. The decision matrix and pharmacogenetic information were used to identify seven drugs for PDM: warfarin, glimepiride, diazepam, amitriptyline, nortriptyline, codeine, and oxycodone. This approach can be applied to other institutional hospitals or other ethnic populations and would be helpful for advancing pharmacy practice. Further work is required to assess the practical and potential clinical relevance of pharmacogenetic variations on drugs of interest before the implementation of PDM. Conclusion. A decision matrix helped identify drugs for which PDM provides the greatest potential benefit at one Korean hospital. Amitriptyline, Anticonvulsants, Antidepressants, Antidiabetic agents, Anxiolytics, sedatives and hypnotics, Asians, Codeine, Decision-making, Diazepam, Glimepiride, Hospitals, Metabolism, Methodology, Nortriptyline, Opiates, Oxycodone, Pharmacogenetics, Polymorphism, Race, Toxicity, Warfarin Individualized drug therapy based on patients’ genetic information offers the potential to improve drug efficacy and reduce adverse drug reactions.1 Over the past several decades, pharmacogenetic knowledge about the proteins responsible for drug disposition and effects has been rapidly increasing.2,3 The clinical application of knowledge of the genetic polymorphisms in drugmetabolizing enzymes, transporters, receptors, and other drug targets will help overcome the interindividual variability in drug responses. Pharmacogenomics aims to elucidate the genetic basis for the difference in drug responses for the purpose of optimizing drug therapy.4,–6 Current approaches to therapeutic drug monitoring (TDM) do not fully address pharmacodynamic variabilities in patients’ response to drug therapy.7 Unlike traditional TDM, pharmacogenetic drug monitoring (PDM)—TDM based on patients’ pharmacogenetic information— enables clinicians to optimize dosage regimens in a noninvasive manner before drug administration. In these aspects, PDM would be complementary to the current TDM8 and have a substantial impact on clinical pharmacy practice in the near future.9 PDM requires genotyping of the genes responsible for drug disposition and effects. Genotyping diagnostic kits are being developed, with a few commercial kits already available for the cytochrome P-450 (CYP) isoenzymes 2C19 and 2D6.10 Owing to rapid advances in molecular sequencing technology, the cost of genotyping tests will probably be reduced before the optimization of drug therapy in the health care system. 6 As medication experts, pharmacists may play an important role in interpreting the results of genotyping tests and making recommendations about drug choice and dosage on the basis of a patient’s genotype.7 In this regard, appropriate and logical applications of pharmacogenomic knowledge to clinical pharmacy practice, as well as continuing education in the field of pharmacogenomics, are necessary for the advancement of hospital pharmacy.11 Understanding the variability of drug-metabolizing enzymes among ethnic groups is a major area addressed by pharmacogenetics. The type and frequency of variant alleles linked to alterations of drug response differ among ethnic groups.12 To our knowledge, however, there has been no systematic approach for applying ethnic pharmacogenetic information to improve pharmacy practice in an individual health system’s pharmacy. CYP isoenzymes, which metabolize a large number of drugs, have been extensively studied in pharmacogenetics. 3,7,13 Given the broad information on the ethnic differences of CYP polymorphisms and their roles in drug disposition and effects, we sought to apply the information on the type and frequency of variant alleles of major CYP enzymes in Koreans to pharmacy practice. We developed a decision matrix to identify drugs for which PDM provides the greatest benefit in a hospital setting using the population’s allele frequencies. With this decision matrix, we identified drugs commonly used at Seoul National University Hospital (SNUH) that might be of clinical concern because of potential alterations of metabolic profiles. Terminology Each individual has two alleles for each gene, with one allele on each chromosome of a pair. (Genes are designated in italics, while their corresponding enzymes are designated in roman type.) One allele is inherited from the mother and the other from the father. Genetic variations may occur in none, one, or two of the alleles and involve gene deletion, duplication, or multiplication or single nucleotide polymorphisms (SNPs). Most of the variations in the human genome are SNPs, which cause no changes in amino acids, amino acid substitutions, stop codons and do not alter mRNA splicing. Variant alleles may encode for drug-metabolizing enzymes, with altered catalytic activities including a nonfunctional enzyme. When a specific variant allele occurs in more than 1% of the population, it is called a polymorphism; if the variant rarely occurs, it is called a mutation. Genotype refers to two alleles for the same gene carried by an individual, while phenotype indicates clinical characteristics (i.e., poor, intermediate, extensive, or ultrarapid metabolizer). An allele is designated with an asterisk and a number following the gene name.14 For example, CYP2C19*1 designates a wild-type (normal) allele, whereas CYP2C19*3 designates a mutant allele.14,15 Their genotypes consist of CYP2C19*1/*1 or CYP2C19*3/*3 (homozygous genotype) and CYP2C19*1/*3 (heterozygous genotype). Groundwork Literature reviews We conducted MEDLINE searches and reviewed related articles to identify variant alleles of CYP enzymes and their clinical implications. The factors or conditions favoring PDM were also researched using MEDLINE. Keywords used in these searches included pharmacogenomics, pharmacogenetics, polymorphism, cytochrome P-450, frequency, and criteria. The references in the cited literature were also thoroughly reviewed to search for extended keywords. Data were also obtained on the frequencies of the identified variant alleles and genotypes or phenotypes for these polymorphic CYP enzymes in Korean populations only. Identification of 100 most frequently prescribed drugs at SNUH The information service (IS) at SNUH provided a list of the drugs used in 2004 arranged by prescription frequency, including oral preparations and injectables but not topical agents. The top 100 most frequently prescribed drugs, excluding general i.v. solutions, i.v. electrolytes, albumin, multivitamin and mineral preparations, digestants, antacids, and laxatives, were derived from these data. The IS also provided the number of patients who visited SNUH in 2004 and the number of patients receiving prescriptions for each drug (patients were counted only once). Identification of human CYP enzymes The CYP enzymes that metabolize each of the top 100 drugs were identified using MEDLINE articles, online sources,16 a drug information database,17 and the Drug Information Handbook.18 Classification of dose-dependent adverse drug reactions To determine dose-dependent adverse drug reactions (ADRs), we referred to the sections of the drug information sources that addressed adverse reactions, overdosage, cautions, acute toxicity, and concentrationdependent ADRs.17,18 MEDLINE articles regarding dose-dependent ADRs and their occurrences were also reviewed. The severities of dose-related ADRs were arbitrarily classified into three major groups. Decision matrix Matrix development With reference to the various factors that favor PDM,1,2,7,19 we developed an algorithm to assist pharmacists in identifying drugs whose use might benefit from PDM in a hospital setting using population- and hospital-specific data (Figure 11). Figure 1. Open in new tabDownload slide Decision matrix by which the candidate drugs for which pharmacogenetic drug monitoring (PDM) provides the greatest potential for benefit can be determined. Specific information (purple boxes) is required for answering the question in each step. 1,2,7,19 CYP = cytochrome P-450, ADR = adverse drug reaction.
 aMetabolic capacity of CYP polymorphisms can be either increased (A) or decreased (B).
 bSome prodrugs are bioactivated by CYP enzymes, in which case the clinical outcomes may be reversed as indicated in parentheses.
 cFrequently prescribed drugs differ among institutions. Figure 1. Open in new tabDownload slide Decision matrix by which the candidate drugs for which pharmacogenetic drug monitoring (PDM) provides the greatest potential for benefit can be determined. Specific information (purple boxes) is required for answering the question in each step. 1,2,7,19 CYP = cytochrome P-450, ADR = adverse drug reaction.
 aMetabolic capacity of CYP polymorphisms can be either increased (A) or decreased (B).
 bSome prodrugs are bioactivated by CYP enzymes, in which case the clinical outcomes may be reversed as indicated in parentheses.
 cFrequently prescribed drugs differ among institutions. The uppermost factor considered for the algorithm was whether a drug of interest was largely metabolized by at least one of the common and clinically relevant polymorphic CYP enzymes. The frequencies and types of CYP pharmacogenetic variation differ markedly among ethnic groups. At this step, common CYP polymorphisms that are clinically relevant in a particular ethnic group must be identified. To do this, ethnic pharmacogenetic information, including the frequencies of variant alleles, genotypes, or phenotypes, had to be determined. If the clearance of a drug of interest was not notably affected by CYP metabolism, no further step was taken. Next, the decision steps were divided into two pathways, A and B, with the assumption that individuals with mutant CYP genes might express increased or decreased drug metabolism.12 Some people have duplicate or multiple alleles for CYP2D6, which results in increased enzymatic activity.12 Pathway A determines whether a drug of interest is likely to cause a significant change in mortality, morbidity, or quality of life when used inappropriately (i.e., due to lowered plasma concentration by an increase in CYP activity). At this step, information about target diseases or symptoms is also required. Pathway B determines whether a drug is likely to cause an increased risk of severe ADRs if its plasma concentration increases due to low CYP activity. At this step, information about the occurrence and severity of dose-dependent ADRs can be introduced. For example, poor metabolizers are most likely to experience severe ADRs from drugs with a narrow therapeutic window.2 If a drug did not meet the criteria, no further step was considered. For drugs bioactivated by CYP enzymes, poor metabolizers may be at increased risk of therapeutic failure. If this type of drug has a narrow therapeutic window, ultrarapid metabolizers may be at increased risk of experiencing ADRs (e.g., bioactivation of codeine to morphine by CYP2D6). At the next step, the frequency of drug prescription or the prevalence of target patients is analyzed using hospital-specific data. PDM is a high priority for frequently prescribed drugs because a larger population of people may suffer severe ADRs or therapeutic failure. The cut-off value for frequently used drugs may vary in each institution. By using the steps listed above, the drug candidate for which PDM has the greatest potential for benefit can be determined. Finally, sufficient clinical evidence to link a specific genotype to clinical outcomes (i.e., increased ADRs or decreased efficacy) of a drug should be intensively assessed before PDM is implemented. If the clinical evidence, including prospective clinical relevance of genetic variation, is sufficient, genotype-based dosage optimization or selection of an alternative medication should be seriously considered. When a specific CYP pharmacogenetic variation is highly frequent in a particular ethnic group, an alternative medication that is unaffected by the same genetic variation may be considered.19 PDM candidates at SNUH To examine the usefulness of the proposed decision matrix for the identification of potential PDM candidates, the 100 most frequently prescribed drugs at SNUH in 2004 were applied to our matrix. Ethnic pharmacogenetic information CYP2C9*2 and CYP2C9*3 are common and clinically important variant alleles that are predictive for CYP2C9 phenotypes with reduced catalytic activity.12,CYP2C19*2 and CYP2C19*3, two null alleles that encode for nonfunctional enzymes, are responsible for almost all the poor metabolizers of CYP2C19 (Tables 11 and 2 2). The phenotypes of CYP2C9 and CYP2C19 can be divided into three groups: poor metabolizers, intermediate metabolizers, and extensive metabolizers. There were discrepancies in the medical literature as to what genotype constitutes an intermediate metabolizer. In this report, we assumed that intermediate metabolizers expressing decreased enzyme activities were either homozygous for two decreased-function alleles or heterozygous for a null allele (i.e., CYP2C9*2/*2, CYP2C9*1/*3, CYP2C9*2/*3, CYP2C19*1/*2 , CYP2C19 *1/*3).23 Table 2. Genotype and Phenotype Frequencies for Selected Cytochrome P-450 (CYP) Alleles Frequency (%) Genotype or Phenotype Catalytic Activity Koreans Catalytic Activity aEstimated for Korean patients. See text for details. Genotype     CYP2C920,–22         *1/*1 Normal 86.9–97.7 65.3         *1/*2 Minor reduction 0 20.4         *2/*2 Moderately reduced 0 0.9         *1/*3 Moderately reduced 2.3–12 11.6         *2/*3 Moderately reduced 0 1.4         *3/*3 Very low 0 0.4     CYP2C1912,23,24         *1/*1 Normal 46.6 73         *1/*2, *1/*3 Moderately reduced 41.7 26         *2/*2,*2/*3, *3/*3 None 11.7 2.1     CYP2D625,27,–33 phenotypea         Ultrarapid metabolizers 2.28 5–10         Extensive metabolizers 69.3 65–80         Intermediate metabolizers 28 10–15         Poor metabolizers 0.44 5–10 Frequency (%) Genotype or Phenotype Catalytic Activity Koreans Catalytic Activity aEstimated for Korean patients. See text for details. Genotype     CYP2C920,–22         *1/*1 Normal 86.9–97.7 65.3         *1/*2 Minor reduction 0 20.4         *2/*2 Moderately reduced 0 0.9         *1/*3 Moderately reduced 2.3–12 11.6         *2/*3 Moderately reduced 0 1.4         *3/*3 Very low 0 0.4     CYP2C1912,23,24         *1/*1 Normal 46.6 73         *1/*2, *1/*3 Moderately reduced 41.7 26         *2/*2,*2/*3, *3/*3 None 11.7 2.1     CYP2D625,27,–33 phenotypea         Ultrarapid metabolizers 2.28 5–10         Extensive metabolizers 69.3 65–80         Intermediate metabolizers 28 10–15         Poor metabolizers 0.44 5–10 Open in new tab Table 2. Genotype and Phenotype Frequencies for Selected Cytochrome P-450 (CYP) Alleles Frequency (%) Genotype or Phenotype Catalytic Activity Koreans Catalytic Activity aEstimated for Korean patients. See text for details. Genotype     CYP2C920,–22         *1/*1 Normal 86.9–97.7 65.3         *1/*2 Minor reduction 0 20.4         *2/*2 Moderately reduced 0 0.9         *1/*3 Moderately reduced 2.3–12 11.6         *2/*3 Moderately reduced 0 1.4         *3/*3 Very low 0 0.4     CYP2C1912,23,24         *1/*1 Normal 46.6 73         *1/*2, *1/*3 Moderately reduced 41.7 26         *2/*2,*2/*3, *3/*3 None 11.7 2.1     CYP2D625,27,–33 phenotypea         Ultrarapid metabolizers 2.28 5–10         Extensive metabolizers 69.3 65–80         Intermediate metabolizers 28 10–15         Poor metabolizers 0.44 5–10 Frequency (%) Genotype or Phenotype Catalytic Activity Koreans Catalytic Activity aEstimated for Korean patients. See text for details. Genotype     CYP2C920,–22         *1/*1 Normal 86.9–97.7 65.3         *1/*2 Minor reduction 0 20.4         *2/*2 Moderately reduced 0 0.9         *1/*3 Moderately reduced 2.3–12 11.6         *2/*3 Moderately reduced 0 1.4         *3/*3 Very low 0 0.4     CYP2C1912,23,24         *1/*1 Normal 46.6 73         *1/*2, *1/*3 Moderately reduced 41.7 26         *2/*2,*2/*3, *3/*3 None 11.7 2.1     CYP2D625,27,–33 phenotypea         Ultrarapid metabolizers 2.28 5–10         Extensive metabolizers 69.3 65–80         Intermediate metabolizers 28 10–15         Poor metabolizers 0.44 5–10 Open in new tab Table 1. Frequency of Selected Cytochrome P-450 (CYP) Alleles Frequency (%) Allelea Catalytic Activity Koreans Caucasians aOnly common variant alleles showing significant clinical effects were indicated. bCYP2D6*14, CYP2D6*18, and CYP2D6*21 (null) alleles were also detected with very low frequencies in Koreans and CYP2D6*8, CYP2D6*11, CYP2D6*12, CYP2D6*15 (null), and CYP2D6*17 (reduced activity) alleles in Caucasians. cDuplication or multiplication of the allele. CYP2C920,–22     *1 Normal 93.4–98.9 82     *2 Moderately reduced 0 11     *3 Very low 1.1–6 7 CYP2C1912,23,24     *1 Normal 67 85.3     *2 None 21 14.7     *3 None 12 0.04 CYP2D612,15,25,26,b     *1 Normal 31.8 36     *2 Slightly reduced 17.3 33     *3 None 0 2     *4 None 0 20     *5 None 5.3 5     *6 None 0 1     *7 None 0 9     *9 Moderately reduced 0 2     *10 Moderately reduced 42.7 2     *16 None 0 2     *1×Nc Increased 0 0.2     *2×N Increased 1.14 0.7 Frequency (%) Allelea Catalytic Activity Koreans Caucasians aOnly common variant alleles showing significant clinical effects were indicated. bCYP2D6*14, CYP2D6*18, and CYP2D6*21 (null) alleles were also detected with very low frequencies in Koreans and CYP2D6*8, CYP2D6*11, CYP2D6*12, CYP2D6*15 (null), and CYP2D6*17 (reduced activity) alleles in Caucasians. cDuplication or multiplication of the allele. CYP2C920,–22     *1 Normal 93.4–98.9 82     *2 Moderately reduced 0 11     *3 Very low 1.1–6 7 CYP2C1912,23,24     *1 Normal 67 85.3     *2 None 21 14.7     *3 None 12 0.04 CYP2D612,15,25,26,b     *1 Normal 31.8 36     *2 Slightly reduced 17.3 33     *3 None 0 2     *4 None 0 20     *5 None 5.3 5     *6 None 0 1     *7 None 0 9     *9 Moderately reduced 0 2     *10 Moderately reduced 42.7 2     *16 None 0 2     *1×Nc Increased 0 0.2     *2×N Increased 1.14 0.7 Open in new tab Table 1. Frequency of Selected Cytochrome P-450 (CYP) Alleles Frequency (%) Allelea Catalytic Activity Koreans Caucasians aOnly common variant alleles showing significant clinical effects were indicated. bCYP2D6*14, CYP2D6*18, and CYP2D6*21 (null) alleles were also detected with very low frequencies in Koreans and CYP2D6*8, CYP2D6*11, CYP2D6*12, CYP2D6*15 (null), and CYP2D6*17 (reduced activity) alleles in Caucasians. cDuplication or multiplication of the allele. CYP2C920,–22     *1 Normal 93.4–98.9 82     *2 Moderately reduced 0 11     *3 Very low 1.1–6 7 CYP2C1912,23,24     *1 Normal 67 85.3     *2 None 21 14.7     *3 None 12 0.04 CYP2D612,15,25,26,b     *1 Normal 31.8 36     *2 Slightly reduced 17.3 33     *3 None 0 2     *4 None 0 20     *5 None 5.3 5     *6 None 0 1     *7 None 0 9     *9 Moderately reduced 0 2     *10 Moderately reduced 42.7 2     *16 None 0 2     *1×Nc Increased 0 0.2     *2×N Increased 1.14 0.7 Frequency (%) Allelea Catalytic Activity Koreans Caucasians aOnly common variant alleles showing significant clinical effects were indicated. bCYP2D6*14, CYP2D6*18, and CYP2D6*21 (null) alleles were also detected with very low frequencies in Koreans and CYP2D6*8, CYP2D6*11, CYP2D6*12, CYP2D6*15 (null), and CYP2D6*17 (reduced activity) alleles in Caucasians. cDuplication or multiplication of the allele. CYP2C920,–22     *1 Normal 93.4–98.9 82     *2 Moderately reduced 0 11     *3 Very low 1.1–6 7 CYP2C1912,23,24     *1 Normal 67 85.3     *2 None 21 14.7     *3 None 12 0.04 CYP2D612,15,25,26,b     *1 Normal 31.8 36     *2 Slightly reduced 17.3 33     *3 None 0 2     *4 None 0 20     *5 None 5.3 5     *6 None 0 1     *7 None 0 9     *9 Moderately reduced 0 2     *10 Moderately reduced 42.7 2     *16 None 0 2     *1×Nc Increased 0 0.2     *2×N Increased 1.14 0.7 Open in new tab It has been reported that CYP2D6 has four distinct phenotypic subgroups: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. 29 Homozygous carriers of two functional alleles are most likely to exhibit the extensive metabolizer phenotype; homozygous carriers of two null alleles, the poor metabolizer phenotype; carriers of more than three functional alleles, the ultrarapid phenotype.29 As with CYP2C9 and CYP2C19, intermediate metabolizers of CYP2D6 were assumed to be either homozygous for two decreasedfunction alleles or heterozygous for a null allele.29,31 In Caucasians, frequency data on CYP2D6 phenotypes were available, 29 but the distribution data of four CYP2D6 phenotypic subgroups in Koreans were unavailable. The genotype frequencies of the four major alleles (CYP2D6*1, CYP2D6*2, CYP2D6*5, and CYP2D6*10) that represent the CYP2D6 phenotypes have not been reported in a large scale of healthy Koreans. Studies on the genotypes of CYP2D6 in a healthy Korean population have been conducted to detect CYP2D6*10, to which the lower catalytic activity of CYP2D6 in Asians, including Koreans, has been attributed.30 Furthermore, the genotypes of CYP2D6 are very diverse and complicated, since they have many clinically important alleles, including multiplicated alleles and more than 13 null alleles. Hence, we estimated the phenotype rather than genotype frequencies for CYP2D6 (Table 22). One of 224 healthy Korean subjects was phenotyped as a poor metabolizer (0.44%), as probed by metoprolol metabolism.27 In contrast, 5–10% of Caucasians have the poor metabolizer phenotype. In a Japanese study, CYP2D6*10 was the most frequent variant CYP2D6 allele, and the subjects with a genotype predicting intermediate metabolism were mainly homozygous for the CYP2D6*10 allele.32 Based on this study, we could conservatively estimate the frequency of Korean CYP2D6 intermediate metabolizers at 28% using the genotype frequency of CYP2D6*10/*10.28 The allele frequency of a duplicated or multiplicated CYP2D6*2 allele in a Korean population was 1.14%. All Korean subjects carrying the CYP2D6*2 × N allele were heterozygous for this allele,25 so the genotype frequency of Korean CYP2D6 ultrarapid metabolizers was estimated to be 2.28%; 5–10% of Caucasians and up to 29% of northeastern African subjects exhibit the ultrarapid metabolizer phenotype. 33 Intermediate metabolizers of CYP2C9, poor and intermediate metabolism of CYP2C19, and intermediate metabolizers of CYP2D6 would be of most clinical concern in a Korean population. Through literature reviews, we found out that CYP3A is active in the metabolism of 36% of marketed drugs33 and markedly varies among individuals.13 We did not consider the CYP3A genetic polymorphisms in the present study for a number of reasons. CYP3A activity is the sum of CYP3A4 and CYP3A5 activities, with minor contributions from CYP3A7 and CYP3A43.13 The genetic variants identified so far in the CYP3A4 gene have only a limited effect on CYP3A-mediated drug metabolism.34,CYP3A5 has two nonfunctional alleles, CYP3A5*3 and CYP3A5*6, which account for marked reduction in CYP3A5 activity.35 The frequency of the CYP3A5*3 allele is 85% in Caucasians, 48% in African Americans, and 77% in Japanese, but the CYP3A5*6 allele occurs less frequently. 35 In Koreans, the frequencies of CYP3A5*1/*1, CYP3A5*1/*3, and CYP3A5*3/*3 genotypes are 5.4%, 33.3%, and 61.3%, respectively.34 In spite of this high frequency of the CYP3A5*3 allele, several studies of midazolam have shown that common CYP3A5 polymorphisms do not seem to have significant clinical consequences.34,36,37 Further studies are required to elucidate the clinical significance of CYP3A5 polymorphisms. In addition, CYP3A4 and CYP3A5 have overlapping substrate specificities, which make them difficult to distinguish.13 Therefore, the scope of our study was limited to clinically important polymorphic CYP enzymes, namely, CYP2C9, CYP2C19, and CYP2D6, which collectively metabolize 43% (16%, 8%, and 19%, respectively) of the drugs currently used.33 Identification of drugs metabolized by polymorphic CYP enzymes Of the 100 most frequently prescribed drugs at SNUH, 9 were largely metabolized by CYP2C9 (aceclofenac, carvedilol, celecoxib, glimepiride, irbesartan, losartan, sertraline, warfarin, and zaltoprofen), 4 by CYP2C19 (diazepam, omeprazole, pantoprazole, and sertraline), and 6 by CYP2D6 (amitriptyline, carvedilol, codeine, nortriptyline, oxycodone, and tamsulosin).16,–18,38,–40 Collectively, 17 drugs are largely metabolized by at least one polymorphic CYP enzyme. Sertraline and carvedilol are extensively oxidized by two polymorphic CYP enzymes. Codeine is a prodrug that is bioactivated to morphine by CYP2D6.17 Of these 17 drugs, 7 have been commonly associated with serious or life-threatening, dose-dependent ADRs (Table 33). Table 3. Classification of Drugs by Severity of Dose-Related ADRsa Enzyme and Drug Dose-Related ADRs Severityb aADRs = adverse drug reactions, CNS = central nervous system. bArbitrary classification, where dose-related ADRs were defined as generally mild (+), serious and uncommon (++), and serious or life-threatening and commonly reported (+++). cSertraline and carvedilol are also largely metabolized by CYP2C19 and CYP2C9, respectively. CYP2C9     Aceclofenac, zaltoprofen, celecoxib3,17,18,39,–41 Platelet dysfunction, renal and gastrointestinal toxicity ++     Warfarin7,17,18,39 Internal or external hemorrhage, hematuria, urgent bleeding +++     Glimepiride17,18,39,42 Hypoglycemia +++     Losartan, irbesartan17,–19,39 Hypotension and tachycardia with very significant overdoses +     Sertraline17,18,39,43,–45,c Somnolence, nausea, vomiting, tachycardia, dizziness, agitation, tremor ++ CYP2C19     Diazepam3,17,18,33,38,39 CNS and respiratory depression, ataxia, lethargy, slurred speech +++     Omeprazole, pantoprazole17,18,38,39 Mild tachycardia, vasodilation, drowsiness, headache + CYP2D6     Amitriptyline, nortriptyline17,18,33,39,40 Agitation, confusion, hallucinations, urinary retention, hypothermia, hypotension, ventricular tachycardia, seizures, respiratory depression +++     Carvedilol17,18,38,46,c Hypotension, bradycardia, CNS toxicity, bronchospasm, hypoglycemia, hyperkalemia ++     Tamsulosin17,18,39 Hypotension, reflex tachycardia, dizziness +     Codeine17,18,39,47 CNS and respiratory depression, gastrointestinal cramping, constipation +++     Oxycodone17,18,39 Nausea, vomiting, CNS and respiratory depression, miosis +++ Enzyme and Drug Dose-Related ADRs Severityb aADRs = adverse drug reactions, CNS = central nervous system. bArbitrary classification, where dose-related ADRs were defined as generally mild (+), serious and uncommon (++), and serious or life-threatening and commonly reported (+++). cSertraline and carvedilol are also largely metabolized by CYP2C19 and CYP2C9, respectively. CYP2C9     Aceclofenac, zaltoprofen, celecoxib3,17,18,39,–41 Platelet dysfunction, renal and gastrointestinal toxicity ++     Warfarin7,17,18,39 Internal or external hemorrhage, hematuria, urgent bleeding +++     Glimepiride17,18,39,42 Hypoglycemia +++     Losartan, irbesartan17,–19,39 Hypotension and tachycardia with very significant overdoses +     Sertraline17,18,39,43,–45,c Somnolence, nausea, vomiting, tachycardia, dizziness, agitation, tremor ++ CYP2C19     Diazepam3,17,18,33,38,39 CNS and respiratory depression, ataxia, lethargy, slurred speech +++     Omeprazole, pantoprazole17,18,38,39 Mild tachycardia, vasodilation, drowsiness, headache + CYP2D6     Amitriptyline, nortriptyline17,18,33,39,40 Agitation, confusion, hallucinations, urinary retention, hypothermia, hypotension, ventricular tachycardia, seizures, respiratory depression +++     Carvedilol17,18,38,46,c Hypotension, bradycardia, CNS toxicity, bronchospasm, hypoglycemia, hyperkalemia ++     Tamsulosin17,18,39 Hypotension, reflex tachycardia, dizziness +     Codeine17,18,39,47 CNS and respiratory depression, gastrointestinal cramping, constipation +++     Oxycodone17,18,39 Nausea, vomiting, CNS and respiratory depression, miosis +++ Open in new tab Table 3. Classification of Drugs by Severity of Dose-Related ADRsa Enzyme and Drug Dose-Related ADRs Severityb aADRs = adverse drug reactions, CNS = central nervous system. bArbitrary classification, where dose-related ADRs were defined as generally mild (+), serious and uncommon (++), and serious or life-threatening and commonly reported (+++). cSertraline and carvedilol are also largely metabolized by CYP2C19 and CYP2C9, respectively. CYP2C9     Aceclofenac, zaltoprofen, celecoxib3,17,18,39,–41 Platelet dysfunction, renal and gastrointestinal toxicity ++     Warfarin7,17,18,39 Internal or external hemorrhage, hematuria, urgent bleeding +++     Glimepiride17,18,39,42 Hypoglycemia +++     Losartan, irbesartan17,–19,39 Hypotension and tachycardia with very significant overdoses +     Sertraline17,18,39,43,–45,c Somnolence, nausea, vomiting, tachycardia, dizziness, agitation, tremor ++ CYP2C19     Diazepam3,17,18,33,38,39 CNS and respiratory depression, ataxia, lethargy, slurred speech +++     Omeprazole, pantoprazole17,18,38,39 Mild tachycardia, vasodilation, drowsiness, headache + CYP2D6     Amitriptyline, nortriptyline17,18,33,39,40 Agitation, confusion, hallucinations, urinary retention, hypothermia, hypotension, ventricular tachycardia, seizures, respiratory depression +++     Carvedilol17,18,38,46,c Hypotension, bradycardia, CNS toxicity, bronchospasm, hypoglycemia, hyperkalemia ++     Tamsulosin17,18,39 Hypotension, reflex tachycardia, dizziness +     Codeine17,18,39,47 CNS and respiratory depression, gastrointestinal cramping, constipation +++     Oxycodone17,18,39 Nausea, vomiting, CNS and respiratory depression, miosis +++ Enzyme and Drug Dose-Related ADRs Severityb aADRs = adverse drug reactions, CNS = central nervous system. bArbitrary classification, where dose-related ADRs were defined as generally mild (+), serious and uncommon (++), and serious or life-threatening and commonly reported (+++). cSertraline and carvedilol are also largely metabolized by CYP2C19 and CYP2C9, respectively. CYP2C9     Aceclofenac, zaltoprofen, celecoxib3,17,18,39,–41 Platelet dysfunction, renal and gastrointestinal toxicity ++     Warfarin7,17,18,39 Internal or external hemorrhage, hematuria, urgent bleeding +++     Glimepiride17,18,39,42 Hypoglycemia +++     Losartan, irbesartan17,–19,39 Hypotension and tachycardia with very significant overdoses +     Sertraline17,18,39,43,–45,c Somnolence, nausea, vomiting, tachycardia, dizziness, agitation, tremor ++ CYP2C19     Diazepam3,17,18,33,38,39 CNS and respiratory depression, ataxia, lethargy, slurred speech +++     Omeprazole, pantoprazole17,18,38,39 Mild tachycardia, vasodilation, drowsiness, headache + CYP2D6     Amitriptyline, nortriptyline17,18,33,39,40 Agitation, confusion, hallucinations, urinary retention, hypothermia, hypotension, ventricular tachycardia, seizures, respiratory depression +++     Carvedilol17,18,38,46,c Hypotension, bradycardia, CNS toxicity, bronchospasm, hypoglycemia, hyperkalemia ++     Tamsulosin17,18,39 Hypotension, reflex tachycardia, dizziness +     Codeine17,18,39,47 CNS and respiratory depression, gastrointestinal cramping, constipation +++     Oxycodone17,18,39 Nausea, vomiting, CNS and respiratory depression, miosis +++ Open in new tab Drug usage and estimation of poor, intermediate, and ultrarapid metabolizers The number of patients likely to be affected by CYP genetic variations at SNUH annually was estimated using population frequency and hospital-specific data (Table 44). In 2004, 291,526 patients visited SNUH, 34,983 (12%) of whom were likely poor metabolizers of CYP2C19. The total number of patients who received one of the seven drugs was 32,311 (11.1% of all patients). Among these patients, 1,237 (3.83%) were estimated to be poor metabolizers; 8,554 (26.5%), intermediate metabolizers; and 309 (0.96%), ultrarapid metabolizers. Of the seven drug candidates for PDM, diazepam was the most frequently prescribed (9,808 patients, 3.4% of all patients). Of these patients, 1,177 (12%) were estimated to be poor metabolizers of CYP2C19. Table 4. Poor, Intermediate, and Ultrarapid Metabolizers of CYP Enzymes at SNUHa No. (%) Patientsc Enzyme and Drug No. (%) Patients Receiving Drugb(n= 291,526) PMs IMs UMs aCYP = cytochrome P-450, SNUH = Seoul National University Hospital, PMs = poor metabolizers, IMs = intermediate metabolizers, UMs = ultrarapid metabolizers. bNumber of patients who received prescriptions for each drug at SNUH in 2004. Each patient was counted only once. cNumbers of PMs, IMs, and UMs were calculated from the population frequency data in Table 22. CYP2C9     Warfarin 4,176 (1.4) 0 301 (7.2) 0     Glimepiride 4,792 (1.6) 0 345 (7.2) 0 CYP2C19     Diazepam 9,808 (3.4) 1,177 (12) 4,119 (42) 0 CYP2D6     Amitriptyline 4,876 (1.7) 21 (0.44) 1,365 (28) 111 (2.28)     Nortriptyline 3,562 (1.2) 16 (0.44) 997 (28) 81 (2.28)     Codeine 3,273 (1.1) 14 (0.44) 916 (28) 75 (2.28)     Oxycodone 1,824 (0.6) 8 (0.44) 511 (28) 42 (2.28)         Total 32,311 (11.1) 1,237 (3.83) 8,554 (26.5) 309 (0.96) No. (%) Patientsc Enzyme and Drug No. (%) Patients Receiving Drugb(n= 291,526) PMs IMs UMs aCYP = cytochrome P-450, SNUH = Seoul National University Hospital, PMs = poor metabolizers, IMs = intermediate metabolizers, UMs = ultrarapid metabolizers. bNumber of patients who received prescriptions for each drug at SNUH in 2004. Each patient was counted only once. cNumbers of PMs, IMs, and UMs were calculated from the population frequency data in Table 22. CYP2C9     Warfarin 4,176 (1.4) 0 301 (7.2) 0     Glimepiride 4,792 (1.6) 0 345 (7.2) 0 CYP2C19     Diazepam 9,808 (3.4) 1,177 (12) 4,119 (42) 0 CYP2D6     Amitriptyline 4,876 (1.7) 21 (0.44) 1,365 (28) 111 (2.28)     Nortriptyline 3,562 (1.2) 16 (0.44) 997 (28) 81 (2.28)     Codeine 3,273 (1.1) 14 (0.44) 916 (28) 75 (2.28)     Oxycodone 1,824 (0.6) 8 (0.44) 511 (28) 42 (2.28)         Total 32,311 (11.1) 1,237 (3.83) 8,554 (26.5) 309 (0.96) Open in new tab Table 4. Poor, Intermediate, and Ultrarapid Metabolizers of CYP Enzymes at SNUHa No. (%) Patientsc Enzyme and Drug No. (%) Patients Receiving Drugb(n= 291,526) PMs IMs UMs aCYP = cytochrome P-450, SNUH = Seoul National University Hospital, PMs = poor metabolizers, IMs = intermediate metabolizers, UMs = ultrarapid metabolizers. bNumber of patients who received prescriptions for each drug at SNUH in 2004. Each patient was counted only once. cNumbers of PMs, IMs, and UMs were calculated from the population frequency data in Table 22. CYP2C9     Warfarin 4,176 (1.4) 0 301 (7.2) 0     Glimepiride 4,792 (1.6) 0 345 (7.2) 0 CYP2C19     Diazepam 9,808 (3.4) 1,177 (12) 4,119 (42) 0 CYP2D6     Amitriptyline 4,876 (1.7) 21 (0.44) 1,365 (28) 111 (2.28)     Nortriptyline 3,562 (1.2) 16 (0.44) 997 (28) 81 (2.28)     Codeine 3,273 (1.1) 14 (0.44) 916 (28) 75 (2.28)     Oxycodone 1,824 (0.6) 8 (0.44) 511 (28) 42 (2.28)         Total 32,311 (11.1) 1,237 (3.83) 8,554 (26.5) 309 (0.96) No. (%) Patientsc Enzyme and Drug No. (%) Patients Receiving Drugb(n= 291,526) PMs IMs UMs aCYP = cytochrome P-450, SNUH = Seoul National University Hospital, PMs = poor metabolizers, IMs = intermediate metabolizers, UMs = ultrarapid metabolizers. bNumber of patients who received prescriptions for each drug at SNUH in 2004. Each patient was counted only once. cNumbers of PMs, IMs, and UMs were calculated from the population frequency data in Table 22. CYP2C9     Warfarin 4,176 (1.4) 0 301 (7.2) 0     Glimepiride 4,792 (1.6) 0 345 (7.2) 0 CYP2C19     Diazepam 9,808 (3.4) 1,177 (12) 4,119 (42) 0 CYP2D6     Amitriptyline 4,876 (1.7) 21 (0.44) 1,365 (28) 111 (2.28)     Nortriptyline 3,562 (1.2) 16 (0.44) 997 (28) 81 (2.28)     Codeine 3,273 (1.1) 14 (0.44) 916 (28) 75 (2.28)     Oxycodone 1,824 (0.6) 8 (0.44) 511 (28) 42 (2.28)         Total 32,311 (11.1) 1,237 (3.83) 8,554 (26.5) 309 (0.96) Open in new tab Discussion There is significant variability in the types and frequencies of allelic variants among ethnic groups, which underlies ethnicity-specific responses to drugs.5 Although ethnic pharmacogenetic information is rapidly increasing, there has been no systematic approach for applying this knowledge to clinical pharmacy practice. We developed a decision matrix that would assist pharmacists in identifying drugs with the greatest potential to benefit from PDM in a hospital setting. Ethnic pharmacogenetic information of polymorphic CYP enzymes, an important class of drug-metabolizing enzymes, was applied to this decision matrix. The most distinct difference among ethnicities is that Koreans are more frequently poor metabolizers of CYP2C19 than are Caucasians (11.7% versus 2.1%), whereas Caucasians are poor metabolizers of CYP2D6 more often than Koreans (5–10% versus 0.44%). Poor metabolizers of CYP2C9 are very rare in both populations. We found that intermediate metabolizers of CYP2C9, poor and intermediate metabolizers of CYP2C19, and intermediate metabolizers of CYP2D6 may be of clinical significance in Koreans. We applied our algorithm to the 100 most frequently prescribed drugs at SNUH and selected 7 drugs with the greatest potential to benefit from PDM, 2 of which are largely metabolized by CYP2C9, one by CYP2C19, and 4 by CYP2D6. Of the estimated 34,983 CYP2C19 poor metabolizers who visited SNUH in 2004, 1,177 patients were prescribed diazepam. It has been shown that the genotype of CYP2C9 markedly affects the pharmacokinetics of warfarin and glimepiride.42 According to one report, the warfarin dose was adjusted to be 56% of the standard dose in patients with the genotype CYP2C9*1/*3 and 23% and 9% of the standard dose in those with CYP2C9*2/*3 and CYP2C9*3/*3, respectively.20 Also, CYP2C9 genetic polymorphisms correlated with a low warfarin dose requirement and with an increased risk of overanticoagulation and major bleeding events during therapy.48,49 Six different genotypes of CYP2C9 showed a significant variability in the mean maintenance dose. Patients carrying at least one variant allele exhibited an increased risk of supratherapeutic International Normalized Ratios and longer times to achieve stable dosing. 49 In a recent prospective pilot trial, fewer adverse events (two) occurred in 18 patients who received a genotype-based warfarin initiation dosage than in 20 patients (six events) receiving a standard initiation dosage (warfarin sodium 5 mg daily), though the study lacked power to show statistical significance.50 Genetic polymorphism of vitamin K epoxide reductase complex subunit 1 (VKORC1), which is a target enzyme of warfarin, is another important determinant of warfarin dose requirements. 51,52 Genetic testing to determine the presence of CYP2C9 and VKORC1 polymorphisms would help to identify a subgroup of patients who may have a higher risk of bleeding events and need a lower starting dosage of warfarin.49 In one study, the plasma concentrations of glimepiride were markedly elevated in poor and intermediate metabolizers of CYP2C9 compared with extensive metabolizers.42 In another study, the total clearance of glimepiride in subjects with the genotype CYP2C9*1/*3 was 43% of that in subjects with CYP2C9*1/*1.20 A case–control study that enrolled 20 diabetic patients hospitalized for severe hypoglycemia and a control group with type 2 diabetes mellitus without a history of severe hypoglycemia showed that CYP2C9*2/*3 and CYP2C9*3/*3 genotypes were associated with severe drug-related hypoglycemia. 53 In both Koreans and Caucasians, poor metabolizers of CYP2C9 are very rare, and a larger sample is warranted to test the association between the genotype CYP2C9*1/*3 and the higher risk of severe drugassociated hypoglycemia. Smaller doses of diazepam have been empirically prescribed for east Asian populations than for Caucasians, since the frequencies of poor and intermediate metabolizers of CYP2C19 are much greater and the mean clearance of diazepam is lower in Koreans. Investigators have studied how diazepam pharmacokinetics are influenced by the genotype of CYP2C19.54,–56 In one study, a larger area under the concentration–time curve (AUC), lower clearance of diazepam, and longer emergence time from general anesthesia were observed in poor metabolizers of CYP2C19 compared with extensive metabolizers. Intermediate metabolizers of CYP2C19 also had a longer emergence time.56 In another study, a significant difference in the plasma elimination half-life values for diazepam was observed among patients with different genotypes of CYP2C19.55 Similarly, doses of tricyclic antidepressants (TCAs) prescribed for east Asians are considerably smaller compared with those prescribed for Caucasians.38 A clear relationship between the genotype of CYP2D6 and TCA pharmacokinetics has been demonstrated.57,–59 The apparent oral clearance of nortriptyline significantly differed based on the number of functional genes.57 The proportion of apparent oral clearances was 1:1:4:5:17 in the groups with 0, 1, 2, 3, and 13 functional genes, respectively. In another study, homozygous carriers of the CYP2D6*10 allele exhibited a significantly higher total AUC, lower apparent oral clearance, and longer mean plasma half-life of nortriptyline than homozygous carriers of the CYP2D6*1 allele.58 TCA dosage recommendations based on the genotype of CYP2D6 have been published.31 The recommended doses of amitriptyline were 73%, 92%, 111%, and 130% of a standard dose in poor, intermediate, extensive, and ultrarapid metabolizers, respectively, compared with 53%, 96%, 119%, and 152% for the respective metabolizers of nortriptyline.31 One study of CYP2D6 polymorphisms on the therapeutic effect and risk of TCA ADRs demonstrated that the frequency of null alleles of the genotype CYP2D6 was higher in patients who experienced ADRs with TCAs than in a random group of depressed patients (44% versus 21%, respectively). 59 Several studies described severe dose-dependent ADRs in poor metabolizers of CYP2D6 who were treated with standard therapeutic doses of TCAs.60 It is not known whether intermediate metabolizers of CYP2D6 have a higher risk of serious ADRs with TCA therapy. Poor metabolizers of CYP2D6 do not show analgesic responses to codeine, which is bioactivated by CYP2D6; therefore, alternative opioid analgesics unaffected by CYP2D6 should be used in these individuals.7 Ultrarapid metabolizers of CYP2D6 receiving codeine might have a higher risk of exaggerated analgesic effects and typical opioidrelated ADRs, probably due to the rapid metabolism to morphine, so a dosage reduction of codeine was recommended in these patients. Two case reports have described ultrarapid metabolizers of CYP2D6 who developed serious ADRs with codeine.61,62 One patient experienced euphoria and very severe pain in the epigastrium, and the other patient developed life-threatening opioid intoxication, including depression of the central nervous and respiratory systems. This ADR should be seriously considered before prescribing codeine for populations with a high rate of CYP2D6 ultrarapid metabolizers, such as northeastern Africans (29%).33 The CYP2D6 ultrarapid metabolizer phenotype is less common in Koreans. As indicated in the last step of our decision matrix, extensive investigation for sufficient clinical evidence supporting PDM is necessary to decide whether a patient receiving a drug of interest requires pharmacogenetic intervention to test for CYP polymorphisms. For most of the seven identified drugs in this study, the influence of CYP polymorphisms on their pharmacokinetic parameters has already been demonstrated. However, few studies have addressed the impact of CYP polymorphisms on clinical implications, such as increased severe ADRs or decreased efficacy. Prospective studies in a general patient population are required to determine whether genotype-based drug therapy is beneficial before the routine use of PDM in a hospital setting. Nonetheless, we should be aware of the potential problems of these drugs and use them cautiously until in-depth evaluation is completed. In particular, we should be more cautious of potential problems when these drugs are concomitantly prescribed with inhibitors or inducers of the CYP enzymes that metabolize them. It would be most desirable to determine the predisposing genetic factors before initiation of drug therapy and select the optimal drug and dosage based on genotyping results. However, the time delay between obtaining genetic test results and drug initiation has been one of the main difficulties in the active introduction of pharmacogenetic intervention. A recent prospective pilot trial demonstrated the feasibility of basing warfarin dosage on the genotype of CYP2C9 in the clinical setting, with approximately four hours passing between blood draw and dosage calculation.50 Meanwhile, genetic testing during drug therapy, particularly when a patient is exhibiting an anomalous response to a drug, would also help define the responsible mechanism and prevent the same adverse event in the future. To our knowledge, this is the first study that used ethnic pharmacogenetic information to promote the implementation of PDM in pharmacy practice. Although the decision matrix developed in this study focused on polymorphic CYP enzymes, the systematic approach described herein may be extended to other drug-metabolizing enzymes, such as the phase II conjugating enzymes. Furthermore, this approach can be applied to and modified for other institutional pharmacies. 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TI - Identifying drugs needing pharmacogenetic monitoring in a Korean hospital
JF - American Journal of Health-System Pharmacy
DO - 10.2146/ajhp050490
DA - 2007-01-15
UR - https://www.deepdyve.com/lp/oxford-university-press/identifying-drugs-needing-pharmacogenetic-monitoring-in-a-korean-qnIu3Uv8Fa
SP - 166
VL - 64
IS - 2
DP - DeepDyve
ER -