Extensive Metabolizer Group Research Articles

The Implications of Cytochrome P450 2D6/CYP2D6 Polymorphism in the Therapeutic Response of Atypical Antipsychotics in Adolescents with Psychosis-A Prospective Study.

The plasma level of antipsychotics and their metabolites depends on the activity of the cytochrome P450 (CYP) system in the liver. This research aims to test the individual response variability to atypical antipsychotic drugs, depending on the activity of the CYP2D6 enzyme. In a prospective, noninterventional study, we included 56 adolescents, 51.79% male, diagnosed with schizophrenia. The patients underwent DNA sampling for genotyping SNP by RT-PCR and CYP* allelic variants using Applied Bio-systems™ TaqMan® Assays Foster City, CA, USA). and clinical and paraclinical assessments. The effectiveness of the therapy was evaluated with the PANSS scores at baseline and 3, 6, and 12 months after the initiation of an atypical antipsychotic treatment. Based on the genotyping results, the patients were divided into slow metabolizers (Group 1), extensive metabolizers (Group 2), and intermediate metabolizers (Group 3). The PANSS score showed a significant decrease in Group 2, compared to Group 3 after 3 (p = 0.02), 6 (p = 0.0009), and 12 months (p < 0.0001). The patients in Group 1 showed high PANSS scores, and those in Group 2 had fewer adverse reactions than the other groups. Assessing the CYP2D6 polymorphism may be useful in clinical pediatric psychiatric practice towards improving clinical results and patients' quality of life.

CYP2C19 metabolizer phenotypes may affect the efficacy of statins on lowering small dense low-density lipoprotein cholesterol of patients with coronary artery disease.

Dyslipidemia is a major cause of arteriosclerotic cardiovascular disease (ASCVD), and low-density lipoprotein cholesterol (LDL-C) is the profile to be reduced to prevent disease progression. Small dense low-density lipoprotein cholesterol (sdLDL-C) has been proven to be a more effective biomarker than LDL-C for ASCVD primary and secondary prevention. CYP2C19 is an important drug metabolism gene. This study aimed to investigate the relationship between sdLDL-C and coronary artery disease (CAD) risk factors and explore the influence of CYP2C19 metabolizer phenotypes on the sdLDL-C lowering efficacy of statins. This study recruited 182 patients with CAD and 200 non-CAD controls. Baseline laboratory indices of fasting blood were detected, including blood lipids, glucose, and creatinine. In addition, LDL-C subfractions were separated and quantified. Gene polymorphisms of SLCO1B1 and CYP2C19 were detected in patients with CAD. The LDL-C subfractions levels of patients with CAD were followed up after statin drug treatment. Total cholesterol, LDL-C, LDLC-2, LDLC-3, LDLC-4, LDLC-5, LDLC-6, LDLC-7, and sdLDL-C levels of patients with CAD were significantly higher than those in non-CAD controls. Meanwhile, sdLDL-C (AUC = 0.838) and LDLC-4 (AUC = 0.835) performed outstandingly in distinguishing patients with CAD from controls. Based on CYP2C19 metabolizer phenotypes, 113 patients with CAD were divided into the extensive metabolizer (EM, n = 49), intermediate metabolizer (IM, n = 52), and poor metabolizer (PM, n = 12) groups. The patients with IM and PM metabolizer phenotypes had better sdLDL-C lowering efficacy after taking statin drugs than patients with EM phenotype (P = 0.0268, FDR = 0.0536). The SLCO1B1 genotype had no significant impact on the efficacy of statins (P = 0.1611, FDR = 0.1611). sdLDL-C and LDLC-4 outperformed other blood lipids such as LDL-C for CAD risk screening. CYP2C19 metabolizer phenotypes had the potential to predict the efficacy of statins in lowering sdLDL-C.

Association of cytochromes P450 3A4*22 and 3A5*3 genotypes and polymorphism with response to simvastatin in hypercholesterolemia patients.

BackgroundsInter-individual variability in response to statin was mainly due to genetic differences. This study aimed to investigate the association of CYP3A4*22 (rs35599367), CYP3A5*3 (rs776746) single nucleotide polymorphism (SNP) with response to simvastatin in hypercholesterolemia patients conducted at King Abdulaziz University hospital (KAUH) in Jeddah, Saudi Arabia.Patients and methodsA total of 274 participants were registered in the current study. Hypercholesterolemic patients taking simvastatin 20 mg (n = 148) and control subjects (n = 126) were tested for rs35599367 and rs776746 genotypes using Custom Taqman ® Assay Probes. Response to simvastatin in these patients was assessed by determination of low density lipoprotein (LDL-C), total cholesterol (TC) and by measuring statin plasma levels using Liquid Chromatography-Mass Spectrometry (LC-MS).ResultsNone of the participants carried a homozygous CYP3A4*22 mutant genotype, while 12 (4.4%) individuals had a heterozygous genotype and 262 (95.6%) had a wild homozygous genotype. The CYP3A5*3 allele was detected in the homozygous mutant form in 16 (5.8%) individuals, while 74 (27.0%) individuals carried the heterozygous genotype and 184 (67.2%) carried the wildtype homozygous genotype. Of the patient group, 15 (11%) were classified as intermediate metabolizers (IMs) and 133 (89%) as extensive metabolizers (EMs). Plasma simvastatin concentrations for the combined CYP3A4/5 genotypes were significantly (P<0.05) higher in the IMs group than in the EMs group. TC and plasma LDL-C levels were also significantly (P<0.05) higher in IMs than in EMs.ConclusionThe present study showed associations between CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) SNP combination genotypes with response to statins in hypercholesterolemia. Patients who had either a mutant homozygous allele for CYP3A5*3 or mutant homozygous and heterozygous alleles for CYP3A4*22 showed increased response to lower TC and LDL-C levels.

The Effect of CYP2D6 Phenotypes on the Pharmacokinetics of Propafenone: A Systematic Review and Meta-Analysis.

Propafenone (PPF) is a class 1C antiarrhythmic agent mainly metabolized by cytochrome (CYP) 2D6, CYP1A2, and CYP3A4. Previous studies have shown that CYP2D6 polymorphism influences the pharmacokinetics (PK) of PPF. However, the small sample sizes of PK studies can lead to less precise estimates of the PK parameters. Thus, this meta-analysis was performed to merge all current PK studies of PPF to determine the effects of the CYP2D6 phenotype more accurately on the PPF PK profile. We searched electronic databases for published studies to investigate the association between the PPF PK and CYP2D6 phenotype. Four PK-related outcomes were included: area under the time–concentration curve (AUC), maximum concentration (Cmax), apparent clearance (CL/F), and half-life (t1/2). A total of five studies were included in this meta-analysis (n = 56). Analyses were performed to compare PK parameters between poor metabolizers (PMs) versus extensive metabolizers (EMs). PPF has a non-linear pharmacokinetics; therefore, analyses were performed according to dose (300 mg and 400 mg). At 300 mg, the AUC mean (95% CI), Cmax, and t1/2 of PPF in PMs were 15.9 (12.5–19.2) µg·h/mL, 1.10 (0.796–1.40) µg/mL, and 12.8 (11.3–14.3) h, respectively; these values were 2.4-, 11.2-, and 4.7-fold higher than those in the EM group, respectively. At 400 mg, a comparison was performed between S- and R-enantiomers. The CL/F was approximately 1.4-fold higher for the R-form compared with the S-form, which was a significant difference. This study demonstrated that CYP2D6 metabolizer status could significantly affect the PPF PK profile. Adjusting the dose of PPF according to CYP2D6 phenotype would help to avoid adverse effects and ensure treatment efficacy.

Effect of major CYP2C19 genetic polymorphisms on Helicobacter pylori eradication based on different treatment regimens.

Helicobacter pylori (H. pylori) infection is a global issue. Its eradication in affected individuals is important to prevent several further complications that may occur if left untreated. Proton pump inhibitors (PPIs) serve an important role in the eradication regimens of H. pylori. PPIs are metabolized primarily through the CYP2C19 enzyme in the liver. Inter-individual variation in the response to eradication treatment may partly be due to variations in the metabolism of PPIs. The aim of this study was to determine whether there was any association between CYP2C19 genetic polymorphisms and the response to eradication therapy amongst Jordanians infected with H. pylori receiving lansoprazole-based regimens. The present study was approved by the Institutional Review Board of The University of Jordan Hospital. A total of 141 patients infected with H. pylori were genotyped for the polymorphisms CYP2C19*2 and CYP2C19*17 using the PCR-restriction fragment length polymorphism assay method. Patients received lansoprazole-based triple or sequential therapy. The assessment of eradication was performed using either a H. pylori stool antigen test or from feedback from patients regarding their improvement. Eradication rates were 84.6% and 64.5% in the intermediate-metabolizer and extensive-metabolizer group, respectively. This difference was not statistically significant. Moreover, no significant association was found between the carriers of the CYP2C19*17 polymorphism and the response to eradication therapy. These findings suggest that there was no significant association between the CYP2C19 genotype and the response to eradication therapy amongst Jordanians infected with H. pylori.

Influence of CYP2C19 Polymorphisms on the Pharmacokinetics of Omeprazole in Elderly Subjects.

Omeprazole blocks the gastric H+ /K+ adenosine triphosphatase, thus inhibiting gastric acid secretion, and is metabolized by cytochrome P450 (CYP) 2C19. Due to the physiological changes in the elderly, there are different pharmacokinetic consequences compared to young people. The aim of this study was to evaluate the pharmacokinetic profiles of omeprazole in 15 elderly participants according to the CYP2C19 genotype. The concentration-time profiles of omeprazole and its metabolites, 5-hydroxy (5-OH) omeprazole and omeprazole sulfone, were similar between the CYP2C19 extensive metabolizer (EM) and intermediate metabolizer groups. In contrast, when comparing the EM group and CYP2C19 poor metabolizer (PM) group, the EM/PM geometric mean ratio (95% confidence interval) of area under the plasma concentration-time curve from time of dosing to the last measurable concentration was 0.52 (0.27-1.01) and that of the IM group was 0.71 (0.32-1.59), indicating that the exposure of omeprazole in the PM group was increased. The exposure of 5-OH omeprazole was significantly decreased in the PM group when compared to the EM group, with an EM/PM geometric mean ratio (95% confidence interval) of 2.20 (1.50-3.22). In conclusion, the tendency of drug exposure according to the CYP2C19 genotype in the elderly and young adults was similar in that the exposure level was highest in the PM group. However, when compared to young adults, the difference between the genotype groups was smaller in the elderly.

Association between CYP2C19 polymorphisms and clinical outcomes in patients undergoing stent procedure for cerebral artery stenosis

We investigated the effect of CYP2C19 polymorphisms on the clinical outcomes of clopidogrel therapy in patients after stenting procedure for cerebral artery stenosis in northeast China. 568 patients performed CYP2C19 genotype screening in the neurosurgery department of our hospital; 154 patients were finally recruited according to the inclusion and exclusion criteria, and followed-up for 6 months. Ischemic events including (1) transient ischemic attack (TIA); (2) stent thrombosis; (3) ischemic stroke; and (4) death were defined as primary clinical endpoints. The frequencies of CYP2C19*1, *2 and *3 alleles in 568 patients were 63.1%, 31.1% and 5.8%, respectively. 154 patients were classified into extensive (65 patients; 42.2%), intermediate (66 patients; 42.9%), and poor (23 patients; 14.9%) metabolizer groups. A χ2 test showed a significant difference in primary clinical endpoints at 6 months (P = 0.04), and a multivariate Cox regression analysis indicated that the CYP2C19 loss-of-function (LOF) alleles associated with post-procedure prognosis. The Kaplan–Meier curve revealed that there was no significant difference in ischemic events between *2 and *3 alleles carriers. Our study verifies that CYP2C19 *2 and *3 have significant impact on the clinical outcomes of clopidogrel therapy in patients with stenting procedure for cerebral artery stenosis in China.

Influence of cytochrome P450 2D6 polymorphism on hippocampal white matter and treatment response in schizophrenia

Cytochrome P450 2D6 (CYP2D6) is expressed at high levels in the brain and plays a considerable role in the biotransformation and neurotransmission of dopamine. This raises the question of whether CYP2D6 variations and its impact on the brain can confer susceptibility to schizophrenia. We investigated the possible links among the CYP2D6 genotype, white matter (WM) integrity of the hippocampus, and the treatment response to antipsychotic drugs in Korean patients with schizophrenia (n = 106). Brain magnetic resonance imaging and genotyping for CYP2D6 were conducted at baseline. The severity of clinical symptoms and the treatment response were assessed using the Positive and Negative Syndrome Scale (PANSS). After genotyping, 43 participants were classified as intermediate metabolizers (IM), and the remainder (n = 63) were classified as extensive metabolizers (EM). IM participants showed significantly higher fractional anisotropy (FA) values in the right hippocampus compared to EM participants. Radial diffusivity (RD) values were significantly lower in the overlapping region of the right hippocampus in the IM group than in the EM group. After 4 weeks of antipsychotic treatment, the EM group showed more improvements in positive symptoms than the IM group. FAs and RDs in the CYP2D6-associated hippocampal WM region were significantly correlated with a reduction in the positive symptom subscale of the PANSS. Greater improvements in positive symptoms were negatively associated with FAs, and positively associated with RDs in the right hippocampal region. The findings suggest that CYP26D-associated hippocampal WM alterations could be a possible endophenotype for schizophrenia that accounts for individual differences in clinical features and treatment responses.

CYP2D6 Genotype-Based Dose Recommendations for Risperidone in Asian People.

The aim of this study was to provide dose recommendations for risperidone in Asian people based on cytochrome P450 enzyme CYP2D6 genotype. First, we investigated the influence of CYP2D6 polymorphism on the pharmacokinetics of risperidone in Chinese patients with schizophrenia. Then, we performed a search for studies covering the relationship between pharmacokinetic parameters of risperidone and CYP2D6 genotype. Pooled pharmacokinetic parameters were meta-analyzed using a random-effects model. Lastly, we calculated the dose adjustment for risperidone based on CYP2D6 genotype for white and Asian people. Significant differences between the extensive metabolizer and intermediate metabolizer groups were observed for dose-adjusted risperidone level, 9-hydroxyrisperidone level, and risperidone/9-hydroxyrisperidone ratio, but not for the total active moiety. Meta-analysis showed that significant differences were observed among the four phenotype groups, including steady state concentration, peak risperidone concentration, and the area under the curve, using the Kruskal-Wallis test. No differences were found in oral clearance. For risperidone, dose recommendations for poor and ultrarapid metabolizers of CYP2D6 for Asians were different compared to that for white people for poor metabolizers (dose adjustment around 45% for white people, while for Asians the risperidone dose should be reduced by 26%). For ultrarapid metabolizers, risperidone dose should be increased by about 33% for white people and 30% for Asians. This was a first attempt to apply pharmacogenetics to suggest dose-regimens for Asian people; further research to replicate and extend these findings is recommended.

Impact of genotype-predicted CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction - a prospective observational study.

The β-1 adrenergic receptor blocker metoprolol is primarily metabolized by the polymorphic enzyme cytochrome P 450 2D6 (CYP2D6), an enzyme with substantial genetic heterogeneity. Our purpose was to investigate the impact of CYP2D6 metabolism on clinical effects and tolerability of metoprolol in patients after myocardial infarction (MI). We included 136 patients with MI discharged on treatment with metoprolol with a recommendation to the general practitioner (GP) to increase the metoprolol dose up to 200mg/day within 2months if possible. At follow-up, metoprolol dosage after up-titration, metoprolol steady-state trough plasma concentrations, hemodynamic parameters, potential metoprolol-induced adverse drug reactions and number of visits to the GP were measured. CYP2D6 genotyping including the reduced-function variant alleles CYP2D6*9, CYP2D6*10 and CYP2D6*41 was performed after end of follow-up. According to the genotype-defined CYP2D6 phenotypes, 30% of the patients were metoprolol extensive metabolizers (EMs), 55% intermediate metabolizers (IMs) and 13% poor metabolizers (PMs; carriers of non-coding and reduced-function variant included). Dose-adjusted metoprolol trough concentrations were significantly higher in IM (2-fold) and PM (6.2-fold) groups vs. the EM group (p< 0.001). Only 35% of patients in the PM group achieved the primary end point, i.e. reaching at least 85% of the expected maximum heart rate (HR) during exercise, compared with 78% in the EM group (p< 0.01), and maximum observed HR at exercise was significantly lower in the PM group vs. the EM group (129 ± 5 vs. 142 ± 2bpm, p< 0.007). In contrast, metoprolol maintenance dose, blood pressure, exercise capacity, number of visits at the GP and frequency and severity of self-reported potential metoprolol-related adverse drug reactions were not significantly different between the groups. Using a comprehensive CYP2D6 genotyping panel, the present study demonstrates a > 6-fold increase of dose-adjusted plasma metoprolol trough concentration in CYP2D6 PMs vs. EMs with a parallel lower increase in achieved maximum HR during exercise but without association between genotype and frequency or severity of self-reported adverse drug effects. This may indicate that CYP2D6 PMs potentially could benefit of the increased plasma concentration per dose in a naturalistic setting.

Observations from a Post-MI Clinic; Does Prevalence of Specific Genetic Polymorphisms in CYP2D6 Influence Adoption of B-Blockers at Clinical Trial Dose Post Myocardial Infarction?

β‐Blockers are first‐line therapy for treatment of heart failure, and for prevention of decline in LV systolic function in post-MI patients. Considerable variability exists in efficacy & tolerability of β‐blockers in HF patients, which may be associated with the genotype of drug-metabolizing enzymes and/or drug targets. Cytochrome P450 2D6 (CYP2D6) is a member of the CYP450 mixed-function oxidase system, which constitutes many important phase I drug metabolizing enzymes and contributes to the metabolism of up to 25% of clinically used drugs. Most genetic polymorphisms to the CYP2D6 gene result in either absent or decreased function of the enzyme activity. Four metabolizer phenotypes are typically used to characterize drug metabolism via CYP2D6: ultra-rapid metabolizer (UM); extensive metabolizer (EM); intermediate metabolizer (IM); and poor metabolizer (PM) phenotypes. Of the 3 β-blockers used for LV systolic dysfunction, CYP2D6 is the predominant metabolizing enzyme of both carvedilol and metoprolol; In contrast, Bisoprolol has a relatively constant β-adrenergic inhibition independent of CYP2D6 genotype. Aims Determine the prevalence of specific genetic CYP2D6 polymorphisms in patients admitted for Acute Coronary Syndromes with systolic dysfunction, and correlate with dose/tolerability or uptitration of metoprolol or carvedilol (BB) treatment. Methods Patients admitted with NSTEMI, ACS or ADHF, with elevated biomarkers had LVEF assessed during index admission. From 10/16/2013 to 07/17/2017, we followed 304 patients admitted for ACS with LVSD in a dedicated ‘post-MI Clinic’ having demonstrated echocardiographic evidence of reduced LVEF ( Results Beta blocker dosage was divided into high (CTD, >150mg daily Metoprolol; >50mg daily Carvedilol; >5mg daily Bisoprolol) or low dose. Within the ultra-rapid / extensive metabolizer (UM/EM) group, 78 patients (41%) were taking high dose BB at 1st visit (35), or successfully uptitrated (43) to high dose in clinic, compared to 9.5% of the (115) patients expressing intermediate metabolizer and poor metabolizer (IM/PM) phenotypes. Within the UM/EM group 36 patients (19%) presented to initial visit on CTD Bisoprolol, with a further 44 (23%) successfully transitioned from low dose BB to CTD Bisoprolol (compared to 12%, and 43%, respectively within the IM/PM group). Conclusion CYP2D6 polymorphisms in patients admitted with ACS and LV systolic dysfunction correlated with tolerability / uptitration of metoprolol and carvedilol, and may be of clinical use in prospectively determining β‐Blocker choice.

The Influence of CYP2D6 Phenotype on the Pharmacokinetic Profile of Atomoxetine in Caucasian Healthy Subjects

Abstract Objective: To analyze a potential phenotypic variation within the studied group based on the pharmacokinetic profile of atomoxetine and its active metabolite, and to further investigate the impact of CYP2D6 phenotype on atomoxetine pharmacokinetics. Methods: The study was conducted as an open-label, non-randomized clinical trial which included 43 Caucasian healthy volunteers. Each subject received a single oral dose of atomoxetine 25 mg. Subsequently, atomoxetine and 4-hydroxyatomoxetine-O-glucuronide (glucuronidated active metabolite) plasma concentrations were determined and a noncompartmental method was used to calculate the pharmacokinetic parameters of both compounds. Further on, the CYP2D6 metabolic phenotype was assessed using the area under the curve (AUC) metabolic ratio (atomoxetine/ 4-hydroxyatomoxetine-O-glucuronide) and specific statistical tests (Lilliefors (Kolgomorov-Smirnov) and Anderson-Darling test). The phenotypic differences in atomoxetine disposition were identified based on the pharmacokinetic profile of the parent drug and its metabolite. Results: The statistical analysis revealed that the AUC metabolic ratio data set did not follow a normal distribution. As a result, two different phenotypes were identified, respectively the poor metabolizer (PM) group which included 3 individuals and the extensive metabolizer (EM) group which comprised the remaining 40 subjects. Also, it was demonstrated that the metabolic phenotype significantly influenced atomoxetine pharmacokinetics, as PMs presented a 4.5-fold higher exposure to the parent drug and a 3.2-fold lower exposure to its metabolite in comparison to EMs. Conclusions: The pharmacokinetic and statistical analysis emphasized the existence of 2 metabolic phenotypes: EMs and PMs. Furthermore, it was proved that the interphenotype variability had a marked influence on atomoxetine pharmacokinetic profile.

Effect of CYP2C19 Gene Polymorphisms on Proton Pump Inhibitor, Amoxicillin, and Levofloxacin Triple Therapy for Eradication of Helicobacter Pylori.

BackgroundThe effects of PPI are variable owing to the CYP2C19 polymorphisms. However, whether the polymorphisms could affect the Hp eradication efficacy of triple therapy is still not clear. The present study aimed to assess the effects of CYP2C19 gene polymorphisms on proton pump inhibitor (PPI), amoxicillin, and levofloxacin triple therapy for Helicobacter pylori (Hp) eradication.Material/MethodsWe randomly assigned 160 Hp-positive patients with chronic gastritis to 2 groups to receive either 20 mg bid omeprazole (OAL group, n=80) or 10 mg bid rabeprazole (RAL group, n=80), combined with 1000 mg bid amoxicillin and 500 mg qd levofloxacin. The 2 groups were treated for 10 days. The CYP2C19 genotypes included wild-type, M1 mutant gene (*2, the mutation of exon 5), and M2 mutant gene (*3, the mutation of exon 4) identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFIP). According to CYP2C19 genotype combinations, the patients were divided into extensive metabolizer (EM), intermediate metabolizer (IM), and poor metabolizer (PM) subgroups. The eradication efficacy of Hp was evaluated by 14C-UBT at 28 days after treatment.ResultsThe trial was completed by 155 patients. Hp eradication rates in OAL and RAL groups were 78.2% and 88.3%, respectively, on per-protocol (PP) analysis, indicating no significant difference (P>0.05). Regarding CYP2C19 genotypes, eradication rates of 60.7%, 84.2%, and 100% were obtained for EM, IM, and PM subgroups, respectively, of the OAL group. EM group eradication rates were significantly lower than IM and PM group values (P<0.05). In the RAL group, no such difference was observed (P>0.05). Hp eradication rates were significantly lower in the EM subgroup of the OAL group compared with that of the RAL group.ConclusionsHp eradication rates were higher in the RAL group than in OAL-treated patients. Interestingly, omeprazole-based therapy was significantly affected by the CYP2C19 genotype, unlike the rabeprazole-based therapy.

Application of Genetic Testing for CYP 450 Polymorphism to Predict Response to Clopidogrel Inpatient Undergoing PCI

AbstractIntroduction: The anti-platelet agent clopidogrel is a commonly prescribed medication in patients in patients who are undergoing percutaneous coronary intervention. Response to clopidogrel varies substantially due to genetic and acquired factors. Patients who experience recurrent cardiovascular ischemic or thrombotic events while taking clopidogrel are typically described as non-responsive or resistant. In our study was planned to assess the utility of pharmaco-genetic testing (CYP2C19) for clopidogrel response and application of the data for modification of anti-platelet regimen accordingly. Methods: This is a prospective nonrandomized ethical committee approved study from our institute. We included the post PCI patients presented with chronic stable angina and acute coronary syndrome (who has less bleeding risk score) with good left ventricular function. Along with the demographic and clinical features, we collected the data of platelet aggregation test (light transmission of aggregometry), CYP2C19 genetic analysis test and clinical outcome at the time of discharge, at 15days of discharge and end of 3 months. CYP2C19 genetic analysis is done by method of DNA based clopidogrel resistance genotyping test. We grouped the cases as extensive metabolizers (EM) and intermediate metabolizers (IM) depending on CYP2C19genetic analysis into two groups.Results: A total of 33 patients are included in this study. Among 33 cases, 25(75.7%) cases are male patients and 8(24.2%) cases are female patient, 18 (54.5%) patients are diabetic Mellitus, 20(60.6%) patient are hypertensives, 7(21.2%) cases are smokers and 5 (15.1%) case are alcoholic. We have diagnosed 20(60.6%) cases of unstable angina and 13(39.4%) cases of chronic stable angina. The average Meheran bleeding risk score is 9.8. Age, risk factors are comparable between the the EM and IM group. But presentation of ACS is more in IM (p=0.001).Follow up at 3 months, one died suddenly (probable stent thrombosis) in EM group. No other MACE occurred in both the groups. Multivariate analysis with binary logistic regression showed that only presentation as ACS is statistically significant in IM (p=0.001). Platelet aggregation showed tendency towards statistical significance (p=0.08) in EM patient. With all other parameters including MACE (p=0.3), there is no statistical significance by multivariate analysis.Conclusion: In our small prospective clinical and genetic analysis of clopidogrel metabolizer status has shown that intermediate metabolizer status of the patient is statistically more in unstable angina (p=0.003). There is tendency for statistically significance between the platelet aggregation test (p=0.08) and extensive metabolizer status of the patient. Whatever may be the status of the clopidogrel metabolizing condition, there is no difference in MACE.

Availability of CYP2D6 genotyping results in general practitioner and community pharmacy medical records.

To investigate the availability of CYP450-2D6 (CYP2D6) genotyping results in general practitioner (GP) and/or community pharmacy records, and the influence thereof on psychotropic CYP2D6 substrate dosing. Primary outcome was the percentage of patients genotyped for CYP2D6 with their genotype/phenotype registered in GP and/or pharmacy records. Secondary outcome was the number of defined daily doses of psychotropic CYP2D6 substrates prescribed after genotyping. For 216 out of 1307 eligible patients, medication overviews could be obtained. Genotyping results were available at GPs for 3.1% and at pharmacies for 5.9%. The average psychotropic CYP2D6 substrate dose was not different between any non-extensive metabolizer group and extensive metabolizer group (all p ≥ 0.486). Valuable information for individualizing psychiatric pharmacotherapy is lost on a large scale.

Impact of CYP2C19 genotype and platelet function on clinical outcome in coronary atherosclerotic heart diseases patients received clopidogrel post percutaneous coronary intervention

Objective: To analyze association of CYP2C19 genotype and platelet function phenotype and their impact on clinical outcomes including bleeding events of coronary artery disease(CAD) patients received clopidogrel post percutaneous coronary intervention(PCI). Methods: Coronary atherosclerotic heart diseases patients underwent elective PCI and coronary stent implantation in Fuwai hospital were prospectively enrolled during May 2012 to April 2013. Patients were assigned into groups by genotype of CYP2C19 (extensive metabolizers, intermediate metabolizers, and poor metabolizers) and phenotype of platelet function (clopidogrel responders, semi-responders, and non-responders). The rates of major adverse cardiovascular events, combined cardiovascular events, and bleeding events were recorded during a at least 12 months follow-up period and compared among above defined groups. The association between genotype or phenotype and clinical outcome was assessed using multivariable Cox regression hazards model. Results: Three hundred and eighty patients received coronary stent implantation and met the inclusion criteria of the study, including 157(41.3%) clopidogrel extensive metabolizers, 176(46.3%) intermediate metabolizers, and 47(12.4%) poor metabolizers according to the genotype grouping; 98(25.8%) were responders to clopidogrel, 149(39.2%) were semi-responders, and 133 (35.0%) were non-responders according to the phenotype grouping. Three hundred and seventy-six patients accomplished follow-up. The highest combined cardiovascular events rate was observed in the poor metabolizers (34.0%(16/47)) as compared to the intermediate metabolizers (19.0%(33/174), P=0.026) and the extensive metabolizers (15.5%(24/155), P=0.005). The highest bleeding events rate was observed in the clopidogrel responders (33.7%(33/98)) as compared to the semi-responders (18.9%(28/149), P=0.008) and non-responders (17.7%(23/130), P=0.008). In multivariable Cox regression analysis, the adjusted risk of cardiovascular death, acute myocardial infarction, stent embolism, target lesion revascularization and angina onset was 2.305 times higher in clopidogrel poor metabolizers than in extensive and semi-metabolizers (95%CI=1.208-4.399, P=0.011). The adjusted HR for bleeding events was 0.540 (95%CI=0.321-0.909, P=0.021) among semi-responders vs. responders, was 0.52 (95%CI=0.301-0.905, P=0.021) among non-responders vs. responders during the 12 months follow-up period. Conclusions: Among CAD patients underwent stenting and clopidogrel treatment, poor CYP2C19 metabolizers group carries a significantly higher risk for combined cardiovascular events than in extensive metabolizers group, while clopidogrel responders patients are at significantly higher risk for bleeding as compared to the semi-responders and non-responders.

Correlation between the CYP2C19 phenotype status and the results of three different platelet function tests in cardiovascular disease patients receiving antiplatelet therapy: an emphasis on newly introduced platelet function analyzer-200 P2Y test.

BackgroundAn association has been reported between CYP2C19 polymorphism and the altered antiplatelet activity of clopidogrel. We investigated this association using the newly introduced platelet function analyzer (PFA)-200 (INNOVANCE PFA-200 System; Siemens Healthcare, Germany) P2Y test.MethodsPolymorphisms of CYP2C19*2, *3, *17 and the degree of inhibition of platelet function were determined in 83 patients. Three different platelet function tests were used to evaluate the degree of platelet inhibition and to check the association with genotype.ResultsThe post-procedure PFA-200 values of extensive metabolizers (EM) patients (285.3±38.8) were higher than those of intermediate metabolizers (IM) and poor metabolizers (PM) patients (227.7±98.3 and 133.7±99.2, respectively; P=0.024). Light transmittance aggregometry (LTA) and the VerifyNow system showed that the post-procedure values for EM patients were lower than those of IM and PM patients (LTA: 24.4±15.7, 34.1±17.6, and 42.2±16.9, respectively, P<0.001; VerifyNow: 133.2±60.5, 171.5±42.6, and 218.7±59.3, respectively, P<0.001). The high residual platelet reactivity (HPR) rates were significantly different among the EM, IM, and PM groups using PFA-200 (PM:IM:EM=82.4:40.6:11.8, P<0.001).ConclusionsApproximately, 59.0% of Korean patients with cardiovascular disease receiving clopidogrel had CYP2C19 loss-of-function genotypes classified as IM or PM, and the frequency was similar to the data from Asian people. The PFA-200, LTA, and VerifyNow platelet function tests revealed evidence of a significant association between the efficacy of clopidogrel and CYP2C19 genotypes.

Genetic Determinants of CYP2C19 Gene *2 and *3 Loss of Function Alleles and Response to Anti Platelet Therapy (Clopidogrel) and Cardiovascular Events. (A Study in Kashmir, North India)

Background: Studies have demonstrated that the mutant *2 and*3 allele of the CYP2C19 loss-of-function polymorphism is associated with diminished metabolization of clopidogrel and an attenuated platelet response to clopidogrel treatment. Since no such study has been conducted in this region, we examined CYP2C19 polymorphism in Acute Coronary Syndrome (ACS) patients on clopidogrel treatment, and its effect on the cardiovascular outcomes. Material and Methods: A total of 100 samples of ACS were included in this study and genotyping of CYP2C19 *2 and *3 gene polymorphisms was performed by a Polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP). Results: The distribution of CYP2C19*2 allele wild *1/*1, Heterozygous *1/*2 and homozygous mutant *2/*2 genotypes was 56%, 34% and 10% respectively while for CYP2C19*3 wild*1/*1 and heterozygous *1/*3 genotypes was 84% and 16% respectively. The frequency of compound heterozygotes (*2/*3) was found in 9% (9 of 100 patients). CYP2C19 *1/*2 allele was found in 03 of 34 (8.8%) patients who had CV events followed by 2 of 10 (20%) patients with mutant genotype CYP2C19*2 (*2/*2) on follow up. In the CYP2C19*3, 31.2% having heterozygous genotype (*1/*3) had CV events as compared to 11.9% with *1/*1 (31% v/s 11.9% p> 0 .05). In the poor-metabolizer group (*2/*2 or *2/*3), 20.1% of patients had CV events on follow up compared to 15.6% in the extensive metabolizer group (*1/*1), whereas in the intermediate group only 10% of patients had CV events (p>0.05). Conclusion: We conclude that patients carrying CYP2C19 loss-of-function alleles had a higher rate of subsequent cardiovascular events than as against those with normal allele. Lack of significant events even in presence of variant alleles justifies us to some extent to continue clopidogrel in our patients

Effects of cytochrome P450 2D6 and 3A5 genotypes and possible coadministered medicines on the metabolic clearance of antidepressant mirtazapine in Japanese patients

A personalized treatment approach should be considered with the second-generation psychiatric drug mirtazapine because of high frequencies of side effects, including characteristic drowsiness. Plasma concentrations of mirtazapine in patients are influenced by many factors, including polymorphic cytochrome P450 enzymes contributing to its transformation to 8-hydroxymirtazapine and N-demethylmirtazapine. The aim of this study was to investigate the determinant factors for individual variations of metabolic clearance of mirtazapine using in vitro and in vivo methods. In vitro analyses using liver microsomes from individual humans in correlation assays and recombinantly expressed P450 enzymes revealed that CYP2D6 was the major contributor to mirtazapine 8-hydroxylation with high affinity, and that CYP3A5 catalyzed N-demethylation in a similar high-capacity manner to that of CYP3A4. CYP1A2 was a minor contributor to mirtazapine 8-hydroxylation. Metabolic clearance of mirtazapine determined in substrate depletion assays and mirtazapine 8-hydroxylation activities in individual liver microsomes were significantly lower in CYP2D6 intermediate metabolizers (IM) and poor metabolizers (PM) than in extensive metabolizers (EM) (p<0.05). Trough plasma concentration/dose ratios of mirtazapine from 14 patients were significantly higher in the CYP2D6 IM/PM group than in the EM group and were also higher in the CYP3A5 poor-expressors group than in the expressors group (p<0.05). Mirtazapine clearance in pooled human liver microsomes was inhibited by quinidine (a CYP2D6 inhibitor), ketoconazole (a CYP3A inhibitor), and in combination with risperidone and duloxetine, possible coadministered medicines. These results suggested that mirtazapine metabolic clearance could be variously influenced by the CYP2D6 and CYP3A5 genotypes and coadministered drugs in clinical patients.

P.1.a.011 Polymorphism of cytochrome P450 2D6 and its clinical significance in a sample of 73 consecutive patients

The activity of cytochrome P-450 enzyme 2D6 (CYP2D6) could be related to heroin-dependent patient satisfaction with methadone maintenance treatment. We sought to compare satisfaction with the usual methadone treatment in patients who are ultrarapid, extensive or poor metabolizers, according to CYP2D6 genotyping.Two hundred and five heroin-dependent patients filled out the Verona Service Satisfaction Scale for methadone maintenance treatment (VSSS-MT), before CYP2D6 genotyping.VSSS-MT overall scores were comparable in the poor metabolizer (N = 9) and extensive metabolizer (N = 185) groups, although they were higher in poor metabolizers and extensive metabolizers taken together than in the ultrarapid metabolizers (N = 11) (p < 0.003). Likewise, ultrarapid metabolizers scored higher than the rest of the sample on the VSSS-MT Basic Interventions subscale (p < 001). Regarding this subscale, no poor metabolizers felt dissatisfied, and ultrarapid metabolizer males (N = 7) reported lower satisfaction than ultrarapid metabolizer females (N = 4) (p < 0.022). Ultrarapid metabolizer genotype accounted for 4.2% of the variance on the VSSS-MT total scores, and 5.0% on the Basic Intervention scores.Heroin-dependent patients who are CYP2D6 ultrarapid metabolizers according to genotyping present deficient satisfaction with methadone maintenance treatment.