CYP2C19 Polymorphisms Research Articles

The Cytochrome P450 2C19 Polymorphism Associated with Major Adverse Cardiovascular Events Risk in Kazak Patients Undergoing Percutaneous Coronary Intervention and Receiving Clopidogrel.

Clopidogrel activity is influenced by cytochrome P450 (CYP450). CYP2C19 polymorphisms vary by ethnicity and region. The aim of the study is to assess the effect of genetic polymorphisms in CYP2C19*2 and *3 and clinical and demographic factors on major adverse cardiovascular events (MACE) in Kazak patients following percutaneous coronary intervention (PCI). 397 patients with PCI treated with clopidogrel and aspirin for at least 12 months were enrolled and outcomes within 1 year were recorded. Approximately 2 ml of peripheral venous blood samples were used for genotype detection. Multivariable logistic regression analyses were performed to identify factors associated with MACE. 95 patients (23.9%) suffered MACE during the period. Logistic regression analysis revealed CYP2C19*2 carriers (odds ratio [OR]: 2.431, 95% [confidence interval] CI: 1.136- 5.275, P = 0.027) and poor metabolizers (OR: 2.128, 95% CI: 0.899-4.82, P = 0.043) to be significantly associated with MACE. The CYP2C19*2 allele variants and poor metabolizers were found to be associated with MACE in a clopidogrel-treated Kazak population with acute coronary syndrome following PCI.

Association of CYP2C19, CYP3A4 and ABCC2 polymorphisms and voriconazole plasma concentrations in Uygur pediatric patients.

Aim: To evaluate the association between CYP2C19, CYP3A4 and ABCC2 polymorphisms and voriconazole plasma concentrations in Uygur pediatric patients with allogeneic hematopoietic stem cell transplantation. Materials & methods: High performance liquid chromatography-mass spectrometry was employed to monitor voriconazole concentrations. First-generation sequencing was performed to detect gene polymorphisms. Results: Voriconazole concentrations of normal metabolizers were significantly higher than those of intermediate (p<0.05) and ultrafast (p<0.001) metabolizers. Patients with ABCC2 GG and GA genotypes exhibited significantly lower voriconazole concentrations compared with patients with the AA genotype (p<0.05). Conclusion: These results demonstrate a significant association between voriconazole concentrations and the CYP2C19 phenotype in Uygur pediatric patients with allogeneic hematopoietic stem cell transplantation.

Vonoprazan With Amoxicillin or Amoxicillin and Clarithromycin for the Treatment of Helicobacter pylori Infection.

To describe the pharmacology, efficacy, safety, and potential role of vonoprazan with amoxicillin or amoxicillin and clarithromycin for the treatment of Helicobacter pylori infection in adults. PubMed, Embase, Cochrane Library, and ClinicalTrials.gov were searched using the terms: (vonoprazan OR voquezna) AND ("H. pylori" OR "Helicobacter pylori") AND amoxicillin with no date limitations up to November 3, 2022. Studies assessing the efficacy and safety of vonoprazan with amoxicillin and/or clarithromycin were included and divided into 3 groups based on different comparisons between treatment regimens used in each group. Ten clinical trials and 17 observational studies were included. Vonoprazan-based therapy demonstrated greater acid inhibition and similar or higher efficacy than proton-pump inhibitor (PPI)-based therapy in treatment-naïve patients and with clarithromycin-resistant infections. Proton-pump inhibitor-based therapies have not reached the desired successful eradication rate of 90% for H. pylori infection. Vonoprazan-based therapies being at least as effective as PPI-based therapies offer an alternative for patients with H. pylori infection. Vonoprazan-based therapies were effective and well tolerated for the treatment of H. pylori infection in adults. These regimens provide an important alternative with prolonged acid inhibition, lower potential for CYP2C19 polymorphism, and at least comparable efficacy and safety versus PPI-based therapies in patients with H. pylori infections. Thus, vonoprazan-based therapy should be considered for certain patients, for example, those with failure to PPI-based treatments.

Pharmacokinetics and bioequivalence evaluation of omeprazole and sodium bicarbonate dry suspensions in healthy Chinese volunteers

Omeprazole and sodium bicarbonate dry suspension are effective treatments for acid-related disorders. This study compared the bioequivalence and safety of the two formulations of omeprazole and sodium bicarbonate powder and assessed how CYP2C19 gene polymorphisms affect pharmacokinetics (PK). A single-center, randomized, single-dose, 2-sequence and 2-period crossover method was performed in forty healthy Chinese subjects. Blood samples were collected after a single dose for PK (AUC0–∞, AUC0–t, and Cmax) analysis. The concentrations of Omeprazole in human plasma were determined by HPLC–MS/MS. Besides, the gene polymorphisms of CYP2C19 were assessed by Sanger sequencing. The geometric mean ratios (90% confidence interval) [GMR (95% CI)] of Test/Reference preparation for Cmax: 95.2% (88.48%, 102.43%), AUC0–t: 97.47% (94.4%, 101.02%), AUC0–∞: 97.68% (94.27%, 101.21%) were within the range of 80.00–125.00%. The non-parametric test showed no statistical difference in Tmax between the two groups (p > 0.05). All drugs were well tolerated, no severe adverse reactions occurred, and no significant differences in adverse events between the two drugs. For CYP2C19 gene polymorphisms, the results showed that of 40 subjects, 12 subjects were extensive metabolizers, 24 were intermediate metabolizers, and 4 were poor metabolizers, the frequency of metabolic genotypes were 30%, 60%, and 10%. And the allele distributions for CYP2C19 were *1, *2, and *3 at 60%, 38.75%, and 1.25%. Both the CYP2C19 alleles and metabolic genotypes were consistent with other studies in Chinese. The results of PK parameters showed that different genotypes of CYP2C19 lead to significant differences in t1/2, AUC0–t, AUC0–∞ and Cmax, but no significant differences in Tmax in each group. At the same time, we confirmed that the PK parameters of the test and reference had no differences between the males and females. This study has shown that the pharmacokinetic parameters of the two formulations are not significantly different, which showed bioequivalence and exemplary safety. CYP2C19 gene polymorphism significantly differed in the PK parameters of omeprazole sodium bicarbonate powder.

Dosage exploration of meloxicam according to CYP2C9 genetic polymorphisms based on a population pharmacokinetic-pharmacodynamic model.

Meloxicam, used for treating inflammatory diseases, shows large differences in metabolism according to CYP2C9 genetic polymorphisms; however, there are few studies on dose regimen setting based on quantitative predictions. The aim of this study was to determine the appropriate meloxicam dose regimen for each genotype through population pharmacokinetic-pharmacodynamic modeling of meloxicam by considering CYP2C9 genetic polymorphisms. For modeling, previously reported pharmacokinetic (plasma concentration)-pharmacodynamic (inhibition of thromboxane B2 generation) data of meloxicam were collected for CYP2C9 genetic polymorphisms (n=43). And these data were mainly used in the modeling process. Through simulations of the established models, steady-state pharmacokinetic-pharmacodynamic profiles were obtained according to meloxicam multiple exposures for each CYP2C9 genotype, and predictions were made based on dose regimen changes. Genetic polymorphisms of CYP2C9 were identified as key covariates that significantly affected pharmacokinetic variability of meloxicam between individuals. The developed meloxicam population pharmacokinetic-pharmacodynamic model predicted pharmacokinetic results of the 7.5mg meloxicam administration groups (n=26) for CYP2C9*1/*1 and *1/*3 as an external validation. The results of model simulation revealed that the differences were 2.39-5.42 times for steady-state mean plasma concentrations and 1.21-1.71 times for the degree of inhibition of thromboxane B2 generation following multiple exposures for CYP2C9*1/*1 versus *1/*13, *1/*3, and *3/*3. This suggested that thromboxane B2 inhibition following increased plasma exposure to meloxicam differed significantly according to CYP2C9 genetic polymorphisms. The dose of meloxicam in CYP2C9*1/*13, *1/*3, and *3/*3 was randomly adjusted to 1.6-15 mg to approximate the mean thromboxane B2 inhibition for CYP2C9*1/*1 at steady state, the dose intervals varied from 24 h to 48 h. The results suggested that clinical dose adjustment of meloxicam would be necessary to account for CYP2C9 genetic polymorphisms and reduce side effects. This study suggests a clearer direction for setting up clinical therapy based on personalized medicine and quantitative predictions for meloxicam.

ASSOCIATION BETWEEN CYP2C19 GENE POLYMORPHISMS AND CARDIOVASCULAR RISK FACTORS IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION

This study aims to investigate CYP2C19 gene polymorphisms and the association between gene polymorphisms with cardiovascular risk factors and major adverse cardiovascular events (MACE) in patients with acute myocardial infarction (AMI). A prospective cross-sectional analysis study involved 86 AMI patients enrolled and assessed CYP2C19 gene polymorphisms with MACE evaluated after three months of AMI treatment. CYP2C19*1*1 genotype accounted for the highest prevalence at 54.7%, which means normal metabolizers phenotype prevalence was the highest. The prevalence of patients with circumflex artery stenting, medical history of taking clopidogrel, percutaneous coronary intervention (PCI), and hypertension in patients with CYP2C19 polymorphism was significantly higher than in those without CYP2C19 polymorphism, 35.9 vs. 10.6, 46.2 vs. 14.9,10.3 vs., and 9.49 vs. 74.5, respectively (p&lt;0.05). In patients with CYP2C19 polymorphisms, using a combination of clopidogrel and aspirin regimen had a 13.6% of cardiovascular mortality, while using ticagrelor and aspirin regimen was 0% (p&gt;0.05). The relationship between CYP2C19 gene polymorphisms and MACE after three months of AMI treatment was not associated. CYP2C19 gene polymorphism is associated with hypertension, medical history of PCI, taking clopidogrel, and circumflex artery stenting injury. This study established the relationship between CYP2C19 gene polymorphism and cardiovascular risk factors in patients with acute myocardial infarction who require testing for this gene polymorphism when suffering from acute myocardial infarction to have a medicine adaptation method. Keywords: Polymorphism, CYP2C19 , Acute Myocardial Infarction, Major Adverse Cardiovascular Events, Percutaneous Coronary Intervention DOI： https://doi.org/10.35741/issn.0258-2724.58.3.11

Fibrinogen-Aα THR312ALA Polymorphism is Associated to Chronic Thromboembolic Pulmonary Hypertension in Turkey.

Chronic thromboembolic pulmonary hypertension is a condition that occurs after mechanical obstruction of the pulmonary arteries by thrombus. Since the frequency and demographics of chronic thromboembolic pulmonary hypertension differ between countries, it is thought that genetic factors may play a role in its development. The aim of this study is to reveal the status of VKORC1, CYP2C9*3, CYP2C9*7, and fibrinogen-Aα THR312ALA gene polymorphisms in chronic thromboembolic pulmonary hypertension patients in Turkey. In this prospective cross-sectional study, a total of 46 chronic thromboembolic pulmonary hypertension patients and 106 healthy volunteers were included. Polymerase chain reaction-restriction fragment length polymorphism method was used to determine candidate gene polymorphisms for chronic thromboembolic pulmonary hypertension. The general population parameters of each locus were calculated, and the relationship between dominant, codominant, and recessive genotype models and chronic thromboembolic pulmonary hypertension was analyzed. For the fibrinogen-Aα gene, those with the THR/THR genotype were found to have a 13.51 (95% CI: 2.688-33.333) times less susceptibility rate to the disease than those with the ALA/THR genotype, the susceptibility of THR/ALA genotype to the disease was 5.026 (95% CI: 1.774-14.242) times more than those with ALA/ALA genotype. There was no difference between patient groups for VKORC1, CYP2C9*3 genes (P >.05). Since the CYP2C9*7 patient group was monomorphic for the ILE allele, the patient/control odds ratio and 95% CI could not be calculated. This study shows that there is an association between the fibrinogen-Aα gene ALA polymorphism at the amino acid position of 312 and the development of chronic thromboembolic pulmonary hypertension, but not between the CYP2C9 and VKORC1 gene polymorphisms.

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Prediction of the Impact of CYP2C19 Polymorphism on Drug-Drug Interaction between Voriconazole and Tacrolimus Using Physiologically-Based Pharmacokinetic Modelling

Effect and safety of anaprazole in the treatment of duodenal ulcers: a randomized, rabeprazole-controlled, phase III non-inferiority study.

The pharmacokinetic and clinical behaviors of many proton pump inhibitors (PPIs) in peptic ulcer treatment are altered by CYP2C19 genetic polymorphisms. This non-inferiority study evaluated the efficacy and safety of the novel PPI anaprazole compared with rabeprazole. We also explored the influence of Helicobacter pylori (H. pylori) infection status and CYP2C19 polymorphism on anaprazole. In this multicenter, randomized, double-blind, double-dummy, positive-drug parallel-controlled, phase III study, Chinese patients with duodenal ulcers were randomized 1:1 to receive rabeprazole 10 mg + anaprazole placebo or rabeprazole placebo + anaprazole 20 mg once daily for 4 weeks. The primary efficacy endpoint was the 4-week ulcer healing rate assessed by blinded independent review. Secondary endpoints were the proportion of patients with improved overall and individual duodenal ulcer symptoms at 4 weeks. Furthermore, exploratory subgroup analysis of the primary endpoint by H. pylori status and CYP2C19 polymorphism was conducted. Adverse events were monitored for safety. Non-inferiority analysis was conducted for the primary endpoint. The study enrolled 448 patients (anaprazole, n = 225; rabeprazole, n = 223). The 4-week healing rates were 90.9% and 93.7% for anaprazole and rabeprazole, respectively (difference, -2.8% [95% confidence interval, -7.7%, 2.2%]), demonstrating non-inferiority of anaprazole to rabeprazole. Overall duodenal ulcer symptoms improved in 90.9% and 92.5% of patients, respectively. Improvement rates of individual symptoms were similar between the groups. Healing rates did not significantly differ by H. pylori status or CYP2C19 genotype for either treatment group. The incidence of treatment-emergent adverse events was similar for anaprazole (72/220, 32.7%) and rabeprazole (84/219, 38.4%). The efficacy of anaprazole is non-inferior to that of rabeprazole in Chinese patients with duodenal ulcers. ClinicalTrials.gov, NCT04215653.

CYP2C8 and CYP2J2 gene variations increase the risk of hypertensive intracerebral hemorrhage

PurposeMany studies have shown that cytochrome P450 (CYP) gene polymorphisms are usually associated with an increased risk of cardiovascular and cerebrovascular diseases. To explore the association of CYP2C8 and CYP2J2 gene polymorphisms with hypertensive intracerebral hemorrhage (HICH) in the Han Chinese population. MethodsForty HICH patients and 40 control subjects were recruited for this study. Two single nucleotide polymorphisms (SNP) (rs1058932, rs2275622) in the CYP2C8 gene and two SNPs (rs2271800, rs1155002) in the CYP2J2 gene were selected for genotyping by direct sequencing. Statistical analysis was applied to examine the effect of genetic variation on HICH. ResultsWe found that variant alleles of CYP2C8 rs1058932 (A) and rs2275622 (C) were both significantly associated with HICH, especially in females. We also found significant associations of CYP2C8 rs1058932 (A) and rs2275622 (C) variant alleles with poor outcomes in HICH patients, especially in males. ConclusionsCYP2C8 gene polymorphisms might increase the risk of HICH in the Han Chinese population and might lead to poor outcomes. This finding adds to the body of literature supporting novel therapeutic strategies for HICH.

Correlation between CYP2C19 Polymorphisms and recurrent risk in Patients with Ischemic Stroke treated with Clopidogrel in Kurdistan region-Iraq

Clopidogrel is a prodrug that must be transformed into an active metabolite by hepatic cytochrome P450 (CYP) isoenzymes to prevent platelet clotting. Polymorphisms of the CYP2C19 gene can cause a reduction or complete loss of CYP2C19 enzyme activity resulting in inhibiting clopidogrel metabolism, effectiveness and increase stroke recurrence risk in ischemic stroke patients. This study aims to investigate the correlation between genetic polymorphisms in CYP2C19*2 and*3 and recurrent risk in patients with ischemic stroke taking clopidogrel 75mg in Kurdistan region –Iraq. This retrospective case-control study was carried out at Kurdistan, Erbil, Medicina medical center, and Rizgary general hospital from January 2021 to August 2021. The blood sample was taken from the participants and tested for genotyping. The collection of data was taken from patients' medical charts in the hospital and patients’ electronic medical records from the neurology clinic. Sixty patients participated, (34) were male and (26) were female, with age range (38-96) years, diagnosed from not more than two years with ischemic stroke and taking 75 mg clopidogrel maintenance dose. Genotyping analysis showed 61.7 % were homozygotes for wild allele *1, the heterozygotes divided into 26.7% (*1/*2) and 6.7 % (*1/*3) genotype, while the homozygotes for mutant alleles CYP2C19*2,*3 distributed in 3.3 %(*2/*2) and 1.7 %(*3/*3). The (*2/*3) was not detected in the study population. A significant relation was found between risk of stroke recurrence with carrying the variant allele CYP2C19 *2, reduced CYP2C19 enzyme metabolic activity, and ACEIs/ARBs usage (P = 0.024, P = 0.039, P=0.24 respectively). On the other hand, there was no significant relationship between the risk of stroke recurrence and carrying the variant allele CYP2C19 *3 (P = 1.000). Ischemic stroke patients treated with clopidogrel and carrying a CYP2C19*2 allele had a higher risk of recurrent stroke as it is associated with reduced the metabolic activity of CYP2C19 enzyme leading to reduction of clopidogrel effect.

Effects of CYP2C19 genetic polymorphism on the pharmacokinetics of tolperisone in healthy subjects

Tolperisone hydrochloride is a centrally-acting muscle relaxant used for relieving spasticities of neurological origin and muscle spasms associated with painful locomotor diseases. It is metabolized to the inactive metabolite mainly by CYP2D6 and, to a lesser extent, by CYP2C19 and CYP1A2. In our previous study, the pharmacokinetics of tolperisone was significantly affected by the genetic polymorphism of CYP2D6, but the wide interindividual variation of tolperisone pharmacokinetics was not explained by genetic polymorphism of CYP2D6 alone. Thus, we studied the effects of CYP2C19 genetic polymorphism on tolperisone pharmacokinetics. Eighty-one subjects with different CYP2C19 genotypes received a single oral dose of 150mg tolperisone with 240mL ofwater, and blood samples were collected up to 12h after dosing. The plasma concentration of tolperisone was measured by a liquid chromatography-tandem mass spectrometry system. The CYP2C19PM group had significantly higher Cmax and lower CL/F values than the CYP2C19EM and CYP2C19IM groups. The AUCinf of the CYP2C19PM group was 2.86-fold and 3.00-fold higher than the CYP2C19EM and CYP2C19IM groups, respectively. In conclusion, the genetic polymorphism of CYP2C19 significantly affected tolperisone pharmacokinetics.

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.

Relationship between CYP2C19 polymorphisms and weight gain in epilepsy patients treated with divalproex sodium: does gender matter?

Introduction: Epilepsy is an unprovoked seizure caused by an abnormal paroxysmal neuronal release in the brain. One of epilepsy treatments is anti-epileptic drug divalproex sodium. It is often prescribed to control seizures but it increases body weight. Weight gain may decrease the effectiveness of epilepsy treatment and cause endocrine disorders. CYP2C19 polymorphism may help physicians map patients vulnerable to weight gain due to divalproex sodium. This study aimed to determine the relationship between CYP2C19 polymorphisms and the incidence of weight gain based on gender in epilepsy patients treated with divalproex sodium. Methods: This cross-sectional study consisted of 17 male and 23 female patients. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to identify CYP2C19 polymorphism which was grouped into: extensive metabolizer, intermediate metabolizer and poor metabolizer. The results were analyzed using Chi-squared test to determine the relationship between CYP2C19 and each variable (gender, age, epilepsy types, valproic acid types, family history of obesity and presence of weight gain) based on of gender. Results: The results showed that there was no statistically significant association between CYP2C19 polymorphisms and gender-based epilepsy patients groups (p&gt;0.05). We found that most of the subjects in this study were women with an increase in body weight by 57.5%. There was no association of CYP2C19 polymorphism with type of divalproex sodium, dose of divalproex sodium, length of treatment, type of epilepsy and family history of obesity. Conclusion: There is no significant association between CYP2C19 polymorphism and weight gain between genders in epilepsy patients.

Analysis of the complications of endocrine therapy with tamoxifen in breast cancer: clinical and pharmacogenetic aspects. Prospective pharmacogenetic cohort study

Background. Tamoxifen is the drug of choice in ER-positive breast cancer (BC) therapy for perimenopausal women and one of the endocrine therapy options for menopausal patients. The pharmacological effect of tamoxifen can be influenced by the activity of cytochrome P450 (CYP) enzymes and P-glycoprotein transporters (Pg), and the genes encoding them have broad polymorphism, affecting serum concentrations of active metabolites. This article presents the overall results of a prospective population-based study of the clinical significance of genetic polymorphism of tamoxifen metabolic enzymes and transporters in breast cancer patients after radical treatment receiving adjuvant endocrine therapy with tamoxifen in outpatient settings during 2018-2019. The study was approved by the Research Ethics Committee of the Russian Medical Academy of Continuing Professional Education.&#x0D; Aim. To analyze the clinical presentation of endocrine therapy with tamoxifen in the adjuvant regimen and to assess the association of polymorphisms of genes encoding cytochrome P450 enzymes and drug transporter proteins with adverse events in BC patients.&#x0D; Materials and methods. One hundred and four women with stage I-III luminal breast cancer receiving adjuvant tamoxifen were examined for the presence of CYP2D6, CYP2C, and the following CYP3A gene polymorphisms: CYP2D6*4, CYP3A5*3, CYP2C9*2, CYP2C9*3, CYP2C19*2, CYP2C19*3, as well as the ABCB1 gene polymorphic marker (C3435T) encoding the P-glycoprotein. The allelic variants were identified using the real-time polymerase chain reaction; the test was performed in the Research Center of the Russian Medical Academy of Continuing Professional Education. The study material was buccal epithelium (double sampling) taken after informed consent signing.&#x0D; Results. Association analysis showed the association of different genetic polymorphisms of CYP2D6, CYP3A5, CYP2C9, and ABCB1 with tamoxifen adverse drug reactions, indicating the clinical significance of these polymorphisms.&#x0D; Conclusion. With the implementation of genetic testing of the studied polymorphisms into the routine clinical practice of oncologists prescribing tamoxifen and gynecologists involved in the follow-up of breast cancer patients receiving endocrine therapy in the adjuvant mode, there will be an opportunity for more effective and safer pharmacotherapy.

Variants in CYP2J2 and CYP2C9 Contribute to Susceptibility of Lung Cancer.

Cytochrome P450 (CYP) enzymes are involved in the metabolism of xenobiotic and carcinogen. In the study, we evaluated the association of CYP2J2 and CYP2C9 variants with lung cancer. Five polymorphisms in CYP2J2 and four polymorphisms in CYP2C9 were genotyped in 507 lung cancer patients and 505 controls with Agena MassARRAY platform. The linkage of variants with lung cancer risk was evaluated by odds ratio (OR) and 95% confidence interval (CI) in genetic models and haplotype analyses. We found that CYP2C9 rs1934967 alleles were associated with lung cancer risk (P < 0.05). In stratified analysis, rs2280274 (women, non-smoker, non-drinker and lymphatic metastasis), rs11207535 (non-smoker and non-drinker), rs10889159 (non-smoker and non-drinker) of CYP2J2, whereas rs1934967 (age ≤ 60m, BMI > 24, squamous carcinoma) of CYP2C9 decreased lung cancer risk (P < 0.05). In addition, the results of linkage disequilibrium (LD) analysis showed that rs2280274|rs4388726 - TG (with adjustment: P = 0.042) of CYP2J2 and rs10509679|rs1934967|rs1934968|rs9332220 - GTGG (without adjustment: P = 0.044) of CYP2C9 were linked with a significantly decreased lung cancer risk. Our results indicated genetic variants in CYP2J2 and CYP2C9 might contribute to the susceptibility of lung cancer in Chinese population.

CYP2C9 Polymorphism Influence in PK/PD Model of Naproxen and 6-O-Desmethylnaproxen in Oral Fluid.

Polymorphisms in CYP2C9 can significantly interfere with the pharmacokinetic (PK) and pharmacodynamic (PD) parameters of nonsteroidal anti-inflammatory drugs (NSAIDs), including naproxen. The present research aimed to study the PK/PD parameters of naproxen and its metabolite, 6-O-desmethylnaproxen, associated with allelic variations of CYP2C9. In our study, a rapid, selective, and sensitive Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) method was developed and validated for the determination of naproxen and its main metabolite, 6-O-desmethylnaproxen, in oral fluid. Naproxen and its main metabolite were separated using a Shim-Pack XR-ODS 75L × 2.0 column and C18 pre-column at 40 °C using a mixture of methanol and 10 mM ammonium acetate (70:30, v/v), with an injection flow of 0.3 mL/min. The total analytical run time was 3 min. The volunteers, previously genotyped for CYP2C9 (16 ancestral—CYP2C9 *1 and 12 with the presence of polymorphism—CYP2C9 *2 or *3), had their oral fluids collected sequentially before and after taking a naproxen tablet (500 mg) at the following times: 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6 8, 11, 24, 48, 72 and 96 h. Significant differences in the PK parameters (* p < 0.05) of naproxen in the oral fluid were: Vd/F (L): 98.86 (55.58−322.07) and 380.22 (261.84−1097.99); Kel (1/h): 0.84 (0.69−1.34) and 1.86 (1.09−4.06), in ancestral and mutated CYP2C9 *2 and/or *3, respectively. For 6-O-desmethylnaproxen, no PK parameters were significantly different between groups. The analysis of prostaglandin E2 (PGE2) proved to be effective and sensitive for PD parameters analysis and showed higher levels in the mutated group (p < 0.05). Both naproxen and its main metabolite, 6-O-desmethylnaproxen, and PGE2 in oral fluid can be effectively quantified using LC-MS/MS after a 500 mg oral dose of naproxen. Our method proved to be effective and sensitive to determine the lower limit of quantification of naproxen and its metabolite, 6-O-desmethylnaproxen, in oral fluid (2.4 ng/mL). All validation data, such as accuracy, precision, and repeatability intra- and inter-assay, were less than 15%. Allelic variations of CYP2C9 may be considered relevant in the PK of naproxen and its main metabolite, 6-O-desmethylnaproxen.

Association of genetic polymorphism of CYP2C19, P2Y12 and response to Clopidogrel in healthy participants.

Association of genetic polymorphism of CYP2C19, P2Y12 and response to Clopidogrel in healthy participants.

Abstract 10926: Warfarin Dosing Algorithms With the Information on Genotype and Amiodarone for Patients Without Extracorporeal Circulation Devices Could Be Beneficial for Those With Left Ventricular Assist Devices

Introduction: Many prediction algorithms for warfarin maintenance dose (WD) were constructed based on the clinical and genetic information of the patients without extracorporeal circulation devices (ECDs). However, it is unclear whether might be useful for the patients with ECD, such as left ventricular assist devices (LVAD), who still require warfarin. Hypothesis: The WD algorithms constructed using non-ECD patients could be useful for LVAD patients. Methods: An observational study, the Human Genome Research Ethics Committee of OU approved (#756), was conducted at the Osaka University (OU) Hospital on 108 LVAD patients receiving warfarin therapy. Genetic polymorphisms of CYP2C9*1, *3, and VKORC1-1639G&gt;A were tested using TaqMan genotyping assay kits. WD was defined as the administered dose during the periods when the PT-INR value was within its target range. We investigated the difference between the actual warfarin dose (AWD) and the calculated warfarin dose (CWD) using an algorithm proposed by the International Warfarin Pharmacogenetics Consortium (IWPC), which we verified with 125 Japanese non-ECD patients previously (Eur J Clin Pharmacol, 75:901). Results: The percentage of patients whose difference between CWD and AWD was within 20% of AWD showed no significant difference between the LVAD and the non-ECD (%; I, LVAD, 41.7, non-ECD, 49.6, p=0.23). The root mean squared percentage error (RMSPE) to the AWD was similar between the groups (%; LVAD, 42, non-ECD, 37). As the algorithm requires if amiodarone is concomitant with warfarin, we probed the effect of the amiodarone dose on the CWD. Interestingly, RMSPE of the LVAD with ≥ 200 mg/day of amiodarone (≥ 200A) was higher compared to those with &lt; 200 mg/day (&lt;200A) and without amiodarone (%; 85.5, 25.9, 36.8). The difference between AWD and CWD of ≥ 200A was significantly higher than &lt;200A (mg/day; 0.87, -0.07; p=0.012). We verified similar tendencies using other algorithms published before. Conclusions: The WD algorithm with the information on genotype and concomitant use of amiodarone for the non-ECD could be beneficial for the LVAD. Besides them, extra careful attention should be required for patients with ≥ 200 mg/day of amiodarone not to have warfarin overdosed.

Effect of CYP2C19 polymorphisms on antidepressant prescription patterns and treatment emergent mania in bipolar disorder

Antidepressant medication is used extensively to treat bipolar depression despite uncertain efficacy. The cytochrome P450 (CYP) 2C19 enzyme metabolize several antidepressants, and polymorphisms in the corresponding gene CYP2C19 influence plasma concentration and hence treatment outcomes in major depressive disorder. Here, we investigate if CYP2C19 polymorphisms are associated with antidepressant treatment patterns and the risk of mania when antidepressants are used in bipolar disorder. Two single nucleotide polymorphisms (rs4244285 and rs12248560) were used to classify 5019 bipolar disorder patients into CYP2C19 metabolic phenotypes ranging from poor to ultra-rapid metabolizers. We used Swedish national registry data 2005–2017 on dispensed medications and inpatient care to estimate risks for early-treatment persistence, treatment discontinuation, switching to a new antidepressant medication, and mania within 3 months of treatment initiation in patients treated with citalopram, escitalopram, sertraline, amitriptyline, and clomipramine. Metabolic phenotypes of CYP2C19 were not robustly associated with the investigated treatment outcomes based on dispense patterns. Slower metabolism was associated with an increased risk of treatment emergent mania for sertraline (hazard ratio [HR] = 1.3, 95% CI = 1.04–1.62, p = 0.02) and the tricyclic antidepressants amitriptyline and clomipramine (HR = 1.46, 95% CI = 1.05–2.02, p = 0.024). In a large study of the impact of CYP2C19 metabolic phenotypes on antidepressant treatment of bipolar depression, we found an association between slower CYP2C19 metabolism and higher risk of treatment emergent mania, which is a step towards personalized risk assessments. There were, however, no clear associations with early treatment persistence, treatment discontinuation, and switching to a new antidepressant.