Increased frequency of cytochrome P450 2D6 poor metabolizers among patients with metoprolol-associated adverse effects

OBJECTIVE: The CYP2D6 genotype is a major determinant of interindividual differences in metoprolol plasma clearance. Cytochrome P450 2D6 (CYP2D6) poor metabolizers exhibit 3- to 10-fold higher plasma concentrations after administration of metoprolol than extensive metabolizers. However, the impact of the CYP2D6 genotype on the occurrence of adverse effects of metoprolol remains controversial. This study addressed whether the incidence of poor metabolizers was higher in patients with metoprolol-associated adverse effects than in the German population at large. METHODS: Approximately 1200 German physicians were asked to report on patients who had experienced pronounced adverse effects in association with administration of metoprolol. CYP2D6 genotypes were determined with a combination of allele-specific polymerase chain reaction and polymerase chain reaction-restriction fragment length polymorphism. The adverse effects, consisting of symptoms related to beta-adrenergic receptor blockade and nonspecific symptoms, were recorded by use of a standardized questionnaire. RESULTS: Twenty-four patients were included in the study. Nine patients had 2 null alleles (poor metabolizer genotype; 38%); the remaining 15 had either 1 null allele (n = 7) or no null alleles (n = 8). Therefore the occurrences of poor metabolizer genotypes in the study population were 4.9- and 5.2-fold more frequent, respectively, than that found in unselected members of the German population in two large studies (P <.0001; chi(2) test). CONCLUSIONS: These data showed that CYP2D6 poor metabolizers had a 5-fold higher risk for development of adverse effects during metoprolol treatment than patients who were not poor metabolizers. Because the absolute risk of adverse effects of metoprolol is unknown, the clinical relevance of the CYP2D6 genotype for metoprolol therapy has to be determined in a prospective manner.     

Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension

OBJECTIVE: Beta-Blocker use can be associated with adverse effects that may have an impact on adherence or harm patients. The commonly prescribed beta-blocker metoprolol is metabolized by the polymorphic cytochrome P450 (CYP) 2D6 enzyme, resulting in widely variable drug exposure. We investigated whether metoprolol plasma concentrations, CYP2D6 polymorphisms, or genotype-derived phenotype was associated with adverse effects or efficacy in patients with hypertension. METHODS: Fifty hypertensive patients received metoprolol by use of a dose-titration algorithm until target blood pressure was reached, intolerable side effects occurred, or maximal daily dose was achieved. CYP2D6 genotype was determined by methods based on polymerase chain reaction-restriction fragment length polymorphism and included 19 allelic variants. Patients were assigned to standard phenotype groups on the basis of genotype. Patients were also assigned activity scores based on functional activity of the alleles. General and dose-limiting adverse events and blood pressure responses were analyzed in relation to metoprolol steady-state pharmacokinetic profile and CYP2D6 genotype-derived phenotype. RESULTS: Poor metabolizers had a significantly longer elimination half-life, higher S-metoprolol area under the plasma concentration-time curve (AUC), and lower oral clearance (P < or = .007 for all parameters). There was a 29.6-fold variability in AUC among extensive metabolizers, which was largely explained by CYP2D6 activity scores (P = .032 for ordered differences in AUC by activity score among extensive metabolizers). Overall general and dose-limiting adverse event rates were 46% and 14%, respectively. General adverse event rates did not differ by AUC quartile (66.7% [95% confidence interval (CI), 35.4%-88.7%] and 41.7% [95% CI, 16.5%-71.4%] in the lowest and highest quartiles, respectively; P = .09 among all quartiles). Dose-limiting adverse event rates were also not different by AUC quartile (16.7% [95% CI, 2.9%-49.1%] and 8.3% [95% CI, 0.4%-40.2%] in the lowest and highest quartiles; P = .35 among all quartiles). Furthermore, adverse event rates did not differ by activity scores or between extensive, intermediate, or poor metabolizers. Antihypertensive response rate and blood pressure changes also were not influenced by differences in plasma concentrations or CYP2D6 genotypes. CONCLUSIONS: As expected, CYP2D6 genotype-phenotype correlates with differences in metoprolol pharmacokinetics. However, there was no association between variable pharmacokinetics or CYP2D6 genotype and beta-blocker-induced adverse effects or efficacy.     

Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test.

BACKGROUND: The ultrarapid metabolizer phenotype of the cytochrome P4502D6 (CYP2D6) enzyme has been considered a relevant cause of nonresponse to antidepressant drug therapy. Prescribing high doses of antidepressants to such patients leads to high concentrations of potentially toxic metabolites and an increased risk for adverse reactions. Normalization of the metabolic status of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with antidepressants. METHODS: Five ultrarapid metabolizers with a CYP2D6 gene duplication or triplication were treated with 25 mg nortriptyline twice a day for 3 consecutive weeks, alone during the first week and concomitantly with the CYP2D6 inhibitor paroxetine 10 mg or 20 mg twice a day, respectively, during the second and third weeks. After the third week, nortriptyline was discontinued and the subjects were treated with paroxetine 20 mg twice a day during the fourth study week. At the end of each study week, the steady-state pharmacokinetic parameters of nortriptyline or paroxetine were determined within the dose interval. In addition, the CYP2D6 phenotype was determined by debrisoquin (INN, debrisoquine) test at baseline and at the end of each study phase. Treatment-related adverse events were recorded during drug administration and for 1 week thereafter. RESULTS: All 5 subjects had very low (subtherapeutic) nortriptyline concentrations after 7 days' treatment with nortriptyline only. Addition of paroxetine 10 mg twice a day to the nortriptyline regimen resulted in a change in all individuals to the "normal" extensive debrisoquine metabolizer phenotype, and therapeutic plasma nortriptyline concentrations were achieved in 4 of 5 subjects after a 3 times mean increase in nortriptyline trough concentration (P =.0011). Doubling the paroxetine dose caused a 15 times mean increase in paroxetine trough concentration (P <.001), indicating strong inhibition by paroxetine of its own metabolism. The high paroxetine concentrations in 2 subjects caused them to have the poor debrisoquine metabolizer phenotype and resulted in a further increase in plasma nortriptyline trough concentration (P =.0099). A strong correlation (rank correlation coefficient [r(s)] = 0.89; P <.0001) was observed between paroxetine and nortriptyline trough concentrations. Paroxetine also significantly decreased the fluctuation of nortriptyline concentrations within the dose interval. One subject discontinued the study after the second study week because of adverse effects; otherwise, the study drugs were well tolerated. CONCLUSIONS: Paroxetine, with a daily dosage from 20 to 40 mg, is an effective tool in normalizing the metabolic status of CYP2D6 ultrarapid metabolizers.     

Impact of CYP2D6 genotype on adverse effects during treatment with metoprolol: a prospective clinical study

OBJECTIVE: Our objective was to study the impact of the cytochrome P450 (CYP) 2D6 polymorphism on the tolerability of metoprolol in a real-life primary care setting. The adverse effects studied comprised effects related to the central nervous system, cardiovascular effects, and sexual dysfunction. METHODS: Patients in whom treatment with metoprolol was considered were enrolled into this prospective, 6-week multicenter study. The dosage of metoprolol was determined on an individual basis and could be freely adjusted on clinical grounds. The indication for treatment was hypertension in about 90% of cases. Systolic and diastolic blood pressure, resting heart rate, and plasma metoprolol and alpha-hydroxymetoprolol concentrations were measured. CYP2D6 genotyping covered alleles *3 to *10 and *41 and the duplications. Possible adverse effects of metoprolol were systematically assessed over a 6-week period by means of standardized rating scales and questionnaires. RESULTS: The final study population comprised 121 evaluable patients (all white patients); among them, there were 5 ultrarapid metabolizers (UMs) (4.1%), 91 extensive metabolizers (EMs) (75%), 21 intermediate metabolizers (IMs) (17%), and 4 poor metabolizers (PMs) (3.3%). Plasma metoprolol concentrations normalized for the daily dose and metoprolol/alpha-hydroxymetoprolol ratios at steady state were markedly influenced by CYP2D6 genotype and displayed a gene-dose effect. The median of the dose-normalized metoprolol concentration was 0.0088 ng/mL, 0.047 ng/mL, 0.34 ng/mL, and 1.34 ng/mL among UMs, EMs, IMs, and PMs, respectively (P<.0001). There was no significant association between CYP2D6 genotype-derived phenotype (EMs and UMs combined versus PMs and IMs combined) and adverse effects during treatment with metoprolol. There was a tendency toward a more frequent occurrence of cold extremities in the PM plus IM group as compared with the EM plus UM group (16.0% versus 4.2%, P=.056; relative risk, 3.8 [95% confidence interval, 1.03--14.3]). CONCLUSIONS: CYP2D6 genotype-derived phenotype was not significantly associated with a propensity for adverse effects to develop during treatment with metoprolol. However, the results concerning tolerability of metoprolol in PMs were inconclusive because of the small number of PMs enrolled.     

Genetic analysis of the CYP2D6 locus in a Hong Kong Chinese population

BACKGROUND: The cytochrome P450 CYP2D6 enzyme debrisoquine 4-hydroxylase metabolizes many different classes of commonly used drugs, such as tricyclic antidepressants and neuroleptics. Genetic polymorphism of the CYP2D6 gene is responsible for pronounced interindividual and interracial differences in the metabolism of these drugs. The CYP2D6*10 allele and its variants are the most frequent alleles found in Orientals, and they are responsible for diminished debrisoquine 4-hydroxylase activity because of the presence of a C(188)-->T mutation in exon 1. METHODS: One hundred nineteen Hong Kong Chinese subjects were genotyped by means of allele-specific PCR, PCR, and restriction enzyme analysis for 10 CYP2D6 alleles (CYP2D6*1, *2, *4D, *5, *8/*14, *10A, *10B, *15, *16, and J9). RESULTS: CYP2D6*10B was the most prevalent allele, and CYP2D6*10/CYP2D6*10 was the most frequent genotype, representing 41.17% [corrected] of the population. CONCLUSIONS: There was no significant difference in the prevalence of the alleles analyzed between our study and the Chinese populations genotyped previously. This is the largest study in terms of the number of CYP2D6 alleles analyzed in an Oriental population and the first one conducted in a Hong Kong Chinese population.     

Pharmacokinetics of mirtazapine: enantioselective effects of the CYP2D6 ultra rapid metabolizer genotype and correlation with adverse effects

Enantiomerically pure drugs and genotyping are promising approaches to achieve optimization in antidepressant therapy. Mirtazapine is a mixed noradrenergic serotoninergic antidepressant used as a racemate. We analyzed pharmacokinetics of its enantiomers in relation to CYP2D6 genotype and in relation to its adverse effects. Mirtazapine was enantioselectively absorbed from the gut with a rate constant of 0.2 min-1 for S+, but 0.08 min-1 for R- mirtazapine. Kinetics of R- mirtazapine was only marginally dependent on CYP2D6 genotype, but total clearance of the S+ enantiomer were 1.3, 2.3, and 3.4 L min-1 in poor, extensive, and ultrarapid metabolizers of CYP2D6 substrates with apparent substantial first-pass metabolism in rapid and ultrarapid metabolizers. Mirtazapine effects on heart rate and blood pressure correlated much more strongly with R- then with S+ concentrations, whereas sedation correlated similarly with both enantiomers. At least concerning some adverse effects, it might be worthwhile to study further mirtazapine enantiospecifically.     

Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for codeine therapy in the context of cytochrome P450 2D6 (CYP2D6) genotype

Codeine is bioactivated to morphine, a strong opioid agonist, by the hepatic cytochrome P450 2D6 (CYP2D6); hence, the efficacy and safety of codeine as an analgesic are governed by CYP2D6 polymorphisms. Codeine has little therapeutic effect in patients who are CYP2D6 poor metabolizers, whereas the risk of morphine toxicity is higher in ultrarapid metabolizers. The purpose of this guideline (periodically updated at http://www.pharmgkb.org) is to provide information relating to the interpretation of CYP2D6 genotype test results to guide the dosing of codeine.     

Low frequency of defective alleles of cytochrome P450 enzymes 2C19 and 2D6 in the Turkish population.

BACKGROUND AND OBJECTIVES: The genetically polymorphic cytochrome P450 enzymes 2Cl9 (CYP2Cl9) and 2D6 (CYP2D6) contribute to the metabolism of about 30% of all drugs. For analysis of the ethnic-related differences in drug disposition and as a preparation for routine genotyping, we examined CYP2C19 and CYP2D6 mutations in a large Turkish population. Methods: CYP2C19 and CYP2D6 alleles were determined with use of genomic deoxyribonucleic acid from 404 unrelated Turkish individuals. CYP2C19 alleles *1 to *5 and CYP2D6 alleles *1 to *12, and *14, *15, and *17 were measured by polymerase chain reaction-restriction fragment length polymorphism assays. RESULTS: From 404 subjects genotyped for CYP2C19, allele frequencies of CYP2C19*1 (wt), CYP2C19*2 (ml), and CYP2C19*3 (m2) were 0.88, 0.12, and 0.004, respectively; mutations m3 and m4 were not found. Four individuals (1.0%) were predicted to be poor metabolizers (CYP2C19*2/*2), a significantly lower frequency compared to Middle European populations. Among 404 subjects genotyped for CYP2D6, most frequent alleles were CYP2D6*1 (allele frequency 0.37), *2 (0.35), *4 (0.11), *10 (0.06), duplications *1x2, *2x2, or *4x2 (0.06), *5 (0.01), and *17(0.01). Overall, six subjects (1.49%) were predicted to be CYP2D6 poor metabolizers, and 35 subjects (8.66%) were predicted to be ultrarapid metabolizers as a result of CYP2D6 gene duplications. CONCLUSION: Obviously, within Europe there is a north-south gradient, with decreasing frequency of poor metabolizers of CYP2C19 and CYP2D6 to the south and a corresponding increase of ultrarapid metabolizers of CYP2D6. As in other white groups, only CYP2C19*2 plays a relevant role for the CYP2C19 poor metabolizer phenotype. The mutational spectrum of CYP2D6 indicated partial ethnic relationships to Asian and African populations.     

Comparison of two CYP2D6 genotyping methods and assessment of genotype-phenotype relationships

BACKGROUND: There have been no published reports comparing the CYP450 GeneChip microarray assay with more standard methods of genetic testing. METHODS: We collected 20-mL blood samples from 236 volunteers for DNA isolation and testing before each individual ingested 60 mg of dextromethorphan, and collected their urine. CYP2D6 alleles *3 to *7, *9, *17, and *41, and multiple CYP2D6 gene copies were tested by allele-specific PCR (AS-PCR), whereas alleles *2 to *4 and *6 to *11 were tested by the Affymetrix CYP450 GeneChip assay. Five of the CYP2D6 alleles (*3, *4, *6, *7, and *9) were tested by both AS-PCR and the CYP450 GeneChip assay in an independent and blinded fashion in 232 of the 236 healthy volunteers. The combined CYP2D6 genotype from both methods was used to divide the population into four subgroups, poor metabolizers (PMs), intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs), based on their relative function and ability to express the CYP2D6 gene. The urinary elimination of dextromethorphan was assessed in each of these CYP2D6 subgroups. RESULTS: The CYP2D6*3, *4, *6, *7, and *9 alleles showed a high degree of concordance between the CYP450 GeneChip and AS-PCR methods (>99% concordance). The mean (SD) of the log[dextromethorphan metabolic ratio (MR)] in the four CYP2D6 subgroups was PM = 0.49 (0.38); IM = -1.24 (0.53); EM = -2.35 (0.61); and UM = -2.43 (0.38). CONCLUSIONS: Oligonucleotide microarray technology is an efficient and reliable way to test for CYP2D6 gene variation based on five alleles compared by separate methods. The methodology is influenced by the quality and amount of DNA present. The log(dextromethorphan MR) is a highly variable index that appears to reflect the crude nature of the dextromethorphan MR as an indicator of CYP2D6 in vivo enzyme activity.     

Quantitative effect of CYP2D6 genotype and inhibitors on tamoxifen metabolism: implication for optimization of breast cancer treatment

BACKGROUND AND OBJECTIVES: N-Desmethyltamoxifen (NDM), a major primary metabolite of tamoxifen, is hydroxylated by cytochrome P450 (CYP) 2D6 to yield endoxifen. Because of its high antiestrogenic potency, endoxifen may play an important role in the clinical activity of tamoxifen. We conducted a prospective trial in 158 patients with breast cancer who were taking tamoxifen to further understand the effect of CYP2D6 genotype and concomitant medications on endoxifen plasma concentrations. METHODS: Medication history, genotype for 33 CYP2D6 alleles, and plasma concentrations of tamoxifen and its metabolites were determined at the fourth month of tamoxifen treatment. RESULTS: By use of a mixture model approach, endoxifen plasma concentration identified 2 phenotypic groups, whereas 4 were defined by the endoxifen/NDM plasma concentration ratio. Three distinct genotype groups were identified in the distribution of endoxifen/NDM ratio: (1) low ratios composed of patients lacking any functional allele (mean, 0.04 +/- 0.02); (2) intermediate ratios represented by patients with 1 active allele (mean, 0.08 +/- 0.04); and (3) high ratios composed of patients with 2 or more functional alleles (mean, 0.15 +/- 0.09). Endoxifen/NDM plasma ratios were significantly different between these groups (P < .001). The mean endoxifen plasma concentration was significantly lower in CYP2D6 extensive metabolizers who were taking potent CYP2D6 inhibitors than in those who were not taking CYP2D6 inhibitors (23.5 +/- 9.5 nmol/L versus 84.1 +/- 39.4 nmol/L, P < .001). CONCLUSION: CYP2D6 genotype and concomitant potent CYP2D6 inhibitors are highly associated with endoxifen plasma concentration and may have an impact on the response to tamoxifen therapy. These iterative approaches may be valuable in the study of other complex genotype-phenotype relationships.     

Cytochrome P450 2D6 and glutathione S-transferase M1 genotypes and migraine

BACKGROUND: Migraine is thought to be a disease of the brain and trigeminovascular system. Migraine patients often claim that stress, food, and beverages trigger their attacks. Chemical substances in these foodstuffs with the property of triggering migraine attacks have not yet been characterised. Cytochrome P450 2D6 (CYP2D6) and glutathione S-transferase M1 (GSTM1) are thought to be present in the brain. They metabolise numerous environmental compounds. The genes exhibit genetic polymorphism that is associated with altered enzyme activity. The aim of this study was to determine if the genotypes of these two enzymes are associated with migraine. MATERIALS AND METHODS: The study included 100 female patients and 245 female controls from the general population. Genomic DNA was isolated from whole blood. Allele specific PCR methods were used to identify the normal CYP2D6*1 allele and the mutated CYP2D6*3 and CYP2D6*4 alleles. Initially all samples were genotyped only for GSTM1 plus (+) and GSTM1 null (-) variants. All samples positive for GSTM1 were further analysed for the presence of allelic variants GSTM1*A and GSTM1*B. RESULTS: None of the CYP2D6 and GSTM1 genotypes was associated with migraine. We observed an odds ratio (OR) for the poor metaboliser genotype of CYP2D6 of 1.4 (95% CI = 0.5-3.6) and for the GSTM1 null genotype of 1.0 (95% CI = 0.6-1.5). CONCLUSION: The results of this study indicate that deficient metabolism because of mutated CYP2D6 alleles or GSTM1 allele variants is not important in the aetiology of migraine.     

The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects

Cytochrome P450 enzymes are essential for the metabolism of many medications. Although this class has more than 50 enzymes, six of them metabolize 90 percent of drugs, with the two most significant enzymes being CYP3A4 and CYP2D6. Genetic variability (polymorphism) in these enzymes may influence a patient's response to commonly prescribed drug classes, including beta blockers and antidepressants. Cytochrome P450 enzymes can be inhibited or induced by drugs, resulting in clinically significant drug-drug interactions that can cause unanticipated adverse reactions or therapeutic failures. Interactions with warfarin, antidepressants, antiepileptic drugs, and statins often involve the cytochrome P450 enzymes. Knowledge of the most important drugs metabolized by cytochrome P450 enzymes, as well as the most potent inhibiting and inducing drugs, can help minimize the possibility of adverse drug reactions and interactions. Although genotype tests can determine if a patient has a specific enzyme polymorphism, it has not been determined if routine use of these tests will improve outcomes.     

Single-step assays to analyze CYP2D6 gene polymorphisms in Asians: allele frequencies and a novel *14B allele in mainland Chinese

BACKGROUND: Cytochrome P450-dependent monooxygenase 2D6 (CYP2D6) activity can be estimated by investigating the metabolism of model drugs or by genotyping the most common CYP2D6 alleles. For Caucasians, the CYP2D6 allele frequencies are well investigated, and single-step assays are available for genotyping, whereas allele analysis in mainland Chinese is limited. METHODS: Two tetra-primer assays and one allele-specific amplification assay were developed to easily genotype the CYP2D6 alleles *8, *10, and *14 previously detected in Asians. Applying these assays in combination with established single-tube assays, we analyzed 223 DNA samples from Chinese volunteers for the CYP2D6 alleles *3, *4, *5, *6, *8, *10, and *14 and for duplication of CYP2D6. RESULTS: Six different alleles were detected in mainland Chinese. The most frequent mutant allele was the intermediate metabolizer allele, CYP2D6*10, with a prevalence of 51.3%, followed by the poor metabolizer alleles CYP2D6*5 (7.2%) and a novel variant of CYP2D6*14. This novel *14B allele (2.0%) differs from the *14 allele by the absence of the C188T substitution and by the additional G1749C substitution. Furthermore, six duplication alleles of CYP2D6 were detected, including one duplication of the *10 allele (*10X2). CONCLUSIONS: The CYP2D6 allele frequencies in mainland Chinese shows some genetic diversity compared with Chinese from other regions: a novel *14B allele, a slightly higher frequency of the *5 allele, and a slightly lower frequency of the *10 allele than in most other Chinese populations.     

Influence of CYP2D6 metabolizer status on ondansetron efficacy in pediatric patients undergoing hematopoietic stem cell transplantation: A case series

Chemotherapy‐induced nausea and vomiting (CINV) is commonly experienced by patients receiving antineoplastic agents prior to hemopoietic stem cell transplant (HSCT). Ondansetron, a 5‐HT3 antagonist metabolized by CYP2D6, is an antiemetic prescribed to treat short‐term CINV, but some patients still experience uncontrolled nausea and vomiting while taking ondansetron. Adult CYP2D6 ultrarapid metabolizers (UMs) are at higher risk for CINV due to rapid ondansetron clearance, but similar studies have not been performed in pediatric patients. We performed a retrospective chart review of 128 pediatric HSCT recipients who received ondansetron for CINV prevention and had CYP2D6 genotyping for 20 alleles and duplication detection. The number of emetic episodes for each patient was collected from the start of chemotherapy through 7 days after HSCT. The average age of the cohort was 6.6 years (range: 0.2–16.7) and included three UMs, 72 normal metabolizers, 47 intermediate metabolizers, and six poor metabolizers. Because UMs are the population at risk for inefficacy, we describe the course of treatment for these three patients, as well as the factors influencing emesis: chemotherapy emetogenicity, diagnosis, and duration of ondansetron administration. The cases described support guidelines recommending non‐CYP2D6 metabolized antiemetics (e.g., granisetron) when a patient is a known CYP2D6 UM, but pediatric studies with a larger sample of CYP2D6 UMs are needed to validate our findings.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

In adults, ondansetron is not as effective for chemotherapy‐induced nausea and vomiting (CINV) in CYP2D6 ultrarapid metabolizers (UMs) compared to non‐UMs. Ondansetron is a medication commonly prescribed to pediatric patients, especially for CINV.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Our study describes the efficacy of ondansetron for CINV in three pediatric CYP2D6 UMs.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Pediatric CYP2D6 UMs experienced more emesis when taking ondansetron for CINV on days where they did not receive opioids than expected, similar to findings in adults.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Based on these findings, at our institution, any patient undergoing a bone marrow transplant that is a CYP2D6 UM will receive granisetron rather than ondansetron; this practice may be applicable to pediatric patients at other institutions.     

Amitriptyline or not, that is the question: pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy

BACKGROUND: Amitriptyline has been replaced in many countries by alternative and more expensive drugs based on claims of improved tolerability and toxicity and despite slightly reduced efficacy. Preliminary studies indicate that adverse effects could be linked to polymorphisms of drug-metabolizing enzymes, but information on their clinical impact remains scanty and includes mainly case reports. We conducted a prospective blinded two-center study seeking correlations between CYP2C19 and CYP2D6 genotypes, drug concentrations, adverse events, and therapy response. METHODS: Fifty Caucasian inpatients with at least medium-grade depressive disorder received amitriptyline at a fixed dose of 75 mg twice a day. Blood samples for concentration monitoring of amitriptyline and nortriptyline were taken weekly until discharge along with evaluations of depression (Hamilton Depression Scale and Clinical Global Impression Scale) and side effect (Dosage Record and Treatment Emergent Symptoms Scale; DOTES) scores. RESULTS: In a ROC analysis, nortriptyline but not amitriptyline concentrations correlated with side effects (DOTES sum score >or=5; area under the curve, 0.733; P = 0.008). Carriers of two functional CYP2D6 alleles had a significantly lower risk of side effects than carriers of only one functional allele (12.1% vs 76.5%; P = 0.00001). The lowest risk was observed for carriers of two functional CYP2D6 alleles combined with only one functional CYP2C19 allele [0 of 13 (0%) vs 9 of 11 (81.8%) for the high-risk group; P = 0.00004]. We found no correlations between drug concentrations or genotypes and therapeutic response. CONCLUSIONS: Combined pharmacogenetic testing for CYP2D6 and CYP2C19 identifies patients with low risk for side effects in amitriptyline therapy and could possibly be used to individualize antidepressive regimens and reduce treatment cost. Identification of genotypes associated with slightly reduced intermediate metabolism may be more important than currently anticipated. It could also be the key to demonstrating cost-effectiveness for CYP2D6 genotyping in critical dose drugs.     

Genetic polymorphisms of drug-metabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 in the Greek population

The aim of the present study was to determine the prevalence of the most common allelic variants of the polymorphic cytochrome P450 (CYP) enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5 and to predict the genotype frequency for each polymorphism in the Greek population. DNA isolated from peripheral blood samples derived from 283 non-related Greek ethnic subjects was used to determine the frequency of CYP2D6*3, CYP2D6*4, CYP2C9*2, CYP2C9*3 and CYP3A5*3 allelic variants by the polymerase chain reaction (PCR)-restriction fragment length polymorphism method, CYP2C19*2 and CYP2C19*3 with allelic specific amplification (PCR-ASA), and CYP2D6*2 (gene duplications) by long PCR analysis. The allelic frequencies (out of a total of 566 alleles) for CYP2D6*3 and CYP2D6*4, were 2.3% and 17.8%, respectively, while gene duplications (CYP2D6*2) were found in 7.4% of the subjects tested. For CYP2C9*2 and CYP2C9*3 polymorphisms the allelic frequencies were 12.9% and 8.13% respectively. For CYP2C19, the *2 polymorphism was present at an allelic frequency of 13.1%, while no subjects were found carrying the CYP2C19*3 allele. Finally, the CYP3A5*3 allele was abundantly present in the Greek population with an allelic frequency of 94.4%. Overall our results show that the frequencies of the common defective allelic variants of CYP2C9, CYP2C19 and CYP3A5 in Greek subjects are similar to those reported for several other Caucasian populations. Finally, a high prevalence of CYP2D6 gene duplication among Greeks was found, a finding that strengthens the idea that a South/North gradient exists in the occurrence of CYP2D6 ultrarapid metabolizers in European populations.     

The impact of the CYP2D6 polymorphism on haloperidol pharmacokinetics and on the outcome of haloperidol treatment

OBJECTIVES: The genetically polymorphic enzyme cytochrome P450 (CYP) 2D6 contributes to the biotransformation of the antipsychotic drug haloperidol. The impact of the polymorphism on haloperidol pharmacokinetics, adverse events, and efficacy was prospectively evaluated under naturalistic conditions in 172 unselected psychiatric inpatients with acute psychotic symptoms. METHODS: Serum trough levels of haloperidol and reduced haloperidol of patients receiving clinically adjusted doses were analyzed on days 3, 14, and 28 after hospital admission. Adverse events such as extrapyramidal symptoms were assessed by standardized rating scales. Efficacy was documented by recording the change in positive and negative schizophrenic symptoms. These parameters were correlated with the CYP2D6 genotype determined by polymerase chain reaction analysis for alleles *1 to *15 and *17. RESULTS: The serum concentrations showed wide interindividual variation. Reduced haloperidol trough levels and haloperidol total clearance correlated significantly with the number of active CYP2D6 genes. In addition, body weight and smoking had significant effects on haloperidol kinetics, whereas age, gender, and comedication showed only slight effects. The ratings for pseudoparkinsonism were significantly higher in poor metabolizers of substrates of CYP2D6. On the other hand, there was a trend toward lower therapeutic efficacy with increasing number of active CYP2D6 genes. CONCLUSIONS: Treatment with haloperidol should be avoided in extremely slow and extremely rapid metabolizers of CYP2D6 substrates. Both genotyping and blood concentration measurement explained only a fraction of the adverse events; about 20 patients would have to be genotyped to achieve a significant benefit in 1 patient. It is interesting that genotyping was at least as good a predictor of adverse events as the measured drug concentrations.     

Impact of the ultrarapid CYP2C19*17 allele on serum concentration of escitalopram in psychiatric patients

Recently, a novel allelic variant of cytochrome P450 2C19 encoding ultrarapid enzyme activity was described (denoted CYP2C19*17). The objective of this study was to evaluate the impact of CYP2C19*17 on serum concentration of escitalopram in psychiatric patients. One hundred and sixty-six patients treated with escitalopram were divided into the following subgroups according to CYP2C19 genotype: CYP2C19*17/*17 (n=7), CYP2C19*1/*17 (n=43), CYP2C19*1/*1 (n=60), CYP2C19*17/def (n=16), CYP2C19*1/def (n=34), and CYP2C19def/def (n=6) (def=defective allele, i.e., CYP2C19*2 or *3). Dose-adjusted serum concentrations of escitalopram were compared using the CYP2C19*1/*1 subgroup as reference. Geometric mean of the escitalopram serum concentration was 42% lower in patients homozygous for CYP2C19*17 (P<0.01) and 5.7-fold higher in subjects homozygous for defective CYP2C19 alleles (P<0.001). Of the heterozygous subgroups, only CYP2C19*1/def was significantly different from CYP2C19*1/*1 (P<0.001). In conclusion, a homozygous CYP2C19*17 genotype is associated with lower serum concentration of escitalopram, which might imply increased risk of therapeutic failure.     

Cytochrome P4502D6 (CYP2D6) gene locus heterogeneity: characterization of gene duplication events

Duplications and multiplications of active CYP2D6 genes can cause ultrarapid drug metabolism and lead to therapeutic failure. Multiple functional and non-functional duplication alleles have been further characterized. Duplications were detected by long-range polymerase chain reaction (PCR), PCR-restriction fragment length polymorphism, and sequence analysis. A PCR fragment encompassing the entire duplicated gene was utilized for detailed characterization. Duplications occurred at 1.3, 5.75, and 2.0% in Caucasian, African American, and racially mixed populations, respectively (n=887 total). Of those 28, 47, and 17% were non-functional CYP2D6*4 x N. Twelve unique duplication alleles were detected: *1 x N, *2 x N, *4 x N, *6 x N, *10 x N, *17 x N, *17 x N[spacer], *29 x N, *35 x N, *43 x N, *45 x N, and a novel non-functional tandem arrangement of a chimeric 2D7/2D6 and *1 gene. All novel duplications except *35 x N were found in African Americans. Accurate identification of gene duplication events is essential to avoid false-positive ultrarapid metabolism assignments and thus, overestimation of predicted activity and increased risk for unwanted adverse events.