Heterozygous Extensive Metabolizers Research Articles

Physiologically based pharmacokinetic modeling of brivaracetam and its interactions with rifampin based on CYP2C19 phenotypes

Brivaracetam (BRV), a third-generation antiepileptic drug (AED), is primarily metabolized through amidase hydrolysis and CYP2C19-mediated hydroxylation in vivo. This study utilized physiologically based pharmacokinetic (PBPK) modeling to explore the pharmacokinetics of BRV and drug interactions between BRV and rifampin (RIF), a CYP2C19 inducer, based on CYP2C19 genetic polymorphisms. A PBPK model of BRV was developed in the general population and in individuals with different CYP2C19 phenotypes by adjusting catalytic rate constants (kcat), and the model was validated with observed clinical data. The model was then extrapolated to predict BRV steady-state plasma concentration in individuals with different CYP2C19 phenotypes, with or without coadministration of RIF. The developed model adequately described BRV exposure in the abovementioned populations. The predicted steady-state area under the curve (AUCτ-ss) increases by 20% in heterozygous extensive metabolizers (hEMs) and 55% in poor metabolizers (PMs), compared to homozygous extensive metabolizer (EMs). When coadministered with RIF, the model predicted the most significant magnitude of drug–drug interaction (DDI) in EMs, while the exposure change of BRV was minimal in PMs. Referencing the recommended concentration for therapeutic drug monitoring (TDM), we concluded that the current clinical maintenance dose of BRV is acceptable regardless of CYP2C19 polymorphisms and coadministration with RIF.

High‐dose dual therapy and CYP2C19 polymorphism in Helicobacter pylori eradication

Background Helicobacter pylori infect about 50% of the world's population. The efficacy of treatment using standard regimens has declined in recent years, mainly due to widespread development of antibiotic resistance. Use of enhanced acid suppression and antibiotics with lower risk to resistance, will shape the future of treatment for H pylori. High-dose dual therapy (HDDT) can overcome the effect of CYP2C19 polymorphism thus enhancing acid suppression and may become an option in H pylori eradication. Objectives To describe the eradication rate and side effects of HDDT in different metaboliser status relating to CYP2C19 polymorphism. Method This is a hospital-based cross-sectional analytic study. A total of 63 H pylori-infected patients diagnosed using rapid urease test and histology were given HDDT for 14 days. Urea breath test was done 4 weeks after cessation of HDDT. CYP2C19 polymorphism was tested using the PCR-RFLP method. The eradication rates of HDDT were compared according to CYP2C19 polymorphism status. Results Over all eradication rate of HDDT was 69.8% (95% CI 57%-80.8%). According to CYP2C19 polymorphism, 26.9% were homozygous extensive metabolisers (HomEM), 66.7% were heterozygous extensive metabolisers (HetEM) and 6.4% were poor metabolisers (PM). Eradication rate of HDDT was 82.4%, 69% and 25% in HomEM, HetEM and PM respectively. Only 16% of patients reported minor side effects. Conclusion Eradication rate of HDDT was fairly satisfactory for both homozygous and heterozygous extensive metaboliser states. This finding suggested that HDDT can overcome the effect of CYP2C19 polymorphism.

Association of cytochrome P2D6 gene polymorphism with the susceptibility of Egyptian patients to systemic sclerosis disease

BackgroundSystemic Sclerosis (SSc) is a chronic disease of the connective tissue caused by an autoimmune inflammatory process. Genetic polymorphisms of cytochrome P2D6 (CYP2D6) enzymes have been implicated in the SSc disease etiopathogenesis. AimOur work was designed to investigate the association between the CYP2D6 gene mutation and the risk of SSc development and its relation to different SSc clinical manifestations. MethodsOne hundred SSc patients were involved in the study and one hundred healthy individuals were included to serve as a contol group.CYP2D6 *1, CYP2D6 *3, CYP2D6 *4 allelic frequencies were analyzed by the Polymerase Chain Reaction- Fragment Length Polymorphism (PCR-RFLP) method. ResultsThe heterozygous extensive metabolizers (CYP2D6 *1/*4) genotype showed a statistically significant risk for developing SSc, assessed by the odds ratio (OR = 2.4, P = 0.003). The homozygous extensive metabolizers (CYP2D6 *1/*1) which are the wild genotypes, were expressed less frequently in SSc patients with a significant difference (OR = 0.23) in comparison with the control group. As for the alleles frequency, a significant increase in the risk of SSc was associated with the mutant CYP2D6 *4 allele frequency (OR = 2.2), indicating that the presence of allele CYP2D6*4 is a risky genetic factor for SSc. Diffuse type systemic sclerosis, gastrointestinal (GIT), cardiac, pulmonary manifestations, positive anti-scleroderma 70, moderate restriction in pulmonary function tests, and abnormal Echocardiographic findings were significantly associated with the (CYP2D6 *1/*4) genotype. ConclusionFinding of the study revealed a higher prevalence of the heterozygotes extensive metabolizers (CYP2D6 *1/*4)genotypes and the mutant alleles (CYP2D6*4) in SSc patients, suggesting the high impact of the CYP2D6 gene mutation on the SSc development.

Population pharmacokinetic analysis of esomeprazole in Japanese subjects with various CYP2C19 phenotypes.

Esomeprazole, the S-isomer of omeprazole, is a proton pump inhibitor which has been approved by over 125 countries, also known as NEXIUM® . Esomeprazole was developed to provide further improvement on efficacy for acid-related diseases with higher systemic bioavailability due to the less first-pass metabolism and lower plasma clearance. Esomeprazole is primarily metabolized by CYP2C19. Approximately <1% of Caucasians and 5%-10% of Asians have absent CYP2C19 enzyme activity. Although the influence of various CYP2C19 phenotypes on esomeprazole pharmacokinetics has been studied, this is the first report in the Japanese population where 27 low CYP2C19 metabolizers were included. In this study, a population PK model describing the PK of esomeprazole was developed to understand the difference of CYP2C19 phenotypes on clearance in the Japanese population. The model quantitatively assessed the influence of CYP2C19 phenotype on esomeprazole PK in healthy Japanese male subjects after receiving repeated oral dosing. The inhibition mechanism of esomeprazole on CYP2C19 activity was also included in the model. CYP2C19 phenotype and dose were found as statistically significant covariates on esomeprazole clearance. The apparent clearance at 10-mg dose was 17.32, 9.77 and 7.37 (L/h) for homozygous extensive metabolizer, heterozygous extensive metabolizer and poor metabolizer subjects, respectively. And the apparent clearance decreased as dose increased. The established population PK model well described the esomeprazole PK and model-predicted esomeprazole PK was in good agreement with external clinical data, suggesting the robustness and applicability of the current model for predicting esomeprazole PK.

Physiologically based pharmacokinetic modeling to predict exposures in healthy Japanese subjects with different CYP2C19 phenotypes: Esomeprazole case study

The objective of this study was to improve the predictive performance of cytochrome P450 (CYP) 2C19 substrates in Japanese subjects using physiologically based pharmacokinetic (PBPK) modeling. Esomeprazole, a CYP2C19 substrate, was selected as a test compound, and the Simcyp simulator was used for pharmacokinetic prediction. The compound file of esomeprazole model developed in healthy Caucasian subjects was applied directly. The population file "Sim-Japanese" in Simcyp was adopted to predict esomeprazole pharmacokinetics in Japanese, while CYP2C19 enzyme abundances in the liver and the gastrointestinal tract for homozygous extensive metabolizers (homo EMs), heterozygous extensive metabolizers (hetero EMs), and poor metabolizers (PMs) were adjusted to be the same as in Caucasians. The PBPK model predicted esomeprazole exposure after 10-, 20-, and 40-mg doses in Japanese subjects within 1.5-fold of observed values in all three -CYP2C19 phenotypes. The reported concentration-time profiles were mostly well-captured within the 95% prediction intervals. By adjusting CYP2C19 enzyme abundances levels in the Japanese population, the systemic exposure of esomeprazole in Japanese subjects can be reasonably extrapolated using a PBPK model developed in Caucasian subjects. This analysis serves as a case application for assessing the predictive performance of CYP2C19 substrate in Japanese subjects by using PBPK modeling approach.

Correlation of CYP2C19 genotypes and Helicobacter pylori infection in children

Objective To evaluate CYP2C19 genotypes distribution in children with Helicobacter pylori (Hp) infection and to know its correlation with gender, age, severity and frequency of clinical symptoms, pathological classification of gastric antral mucosa. Methods Antral mucosas of 214 Hp infection patients who were hospitalized at Beijing Children′s Hospital of Capital Medical University from July 2013 to December 2015 were collected.Genotypes were determined by PCR-sequence specific primer method, which were classified as homozygous extensive metabolizer (HomEM), heterozygous extensive metabolizer (HetEM) and poor metabolizer (PM). The differences in CYP2C19 genotype distribution in gender, age, severity and frequency of clinical symptoms, pathological classification of gastric antral mucosa were analyzed. Results (1)Among 214 Hp infected children, the percentage of HomEM was 48.1%(103/214 cases), HetEM was 46.3%(99/214 cases), and PM was 5.6%(12/214 cases). PM in the CYP2C19 infection patients was lower than that in the normal Han nationality in China, and the difference was statistically significant (P 0.05). (3)There was no statistical difference in severity and frequency of clinical symptoms of CYP2C19 genotypes(all P>0.05). (4)In HomEM group, according to pathological classification of gastric mucosa, there were 14 cases of mild injury, 36 cases of moderate injury and 53 cases of severe injury, respectively.In HetEM group, there were 17 cases of mild injury, 29 cases of moderate injury and 53 cases of severe injury, respectively.In PM group, there were 2 cases of mild injury, 3 cases of moderate injury and 7 cases of severe injury, respectively.There was no statistical difference in the pathological degree of inflammation changes in gastric antral mucosa of CYP2C19 genotypes(all P>0.05). (5)Thirty-five cases didn′t receive treatment, 78 cases received Hp eradication one time and failed, 101 cases received no less than 2 times of unsuccessful Hp eradication.The number of Hp unsuccessful eradications were positively correlated with the degree of pathological inflammation changes(r=0.219, P<0.01). There was obvious difference between the number of Hp unsuccessful eradication and the pathological degree of inflammation changes in gastric antral mucosa (χ2=12.414, P<0.05). Conclusions There was no statistical difference in CYP2C19 genotypes distribution as for different gender, age, severity and frequency of clinical symptoms, pathological classification of gastric antral mucosa and CYP2C19 genotypes.The number of Hp unsuccessful eradication was positively correlated with the degree of pathological inflammation changes. Key words: Helicobacter pylori; CYP2C19 gene; Child

Polymorphism of CYP2C19 gene polymorphism in Patients with Coronary Heart Disease in Chongqing

Objective: To explore the distribution of drug metabolic enzymes CYP2C19 genetic polymorphism in coronary heart disease (CAD) patients of Chongqing. Methods: We have done genotyping to 179 CAD patients taking clopidogrel by gene chip method, analyzed the distribution of genotype and metabotropic phenotype. Results: In this study, a total of six different CYP2C19 genotypes and three metabotropic phenotypes were detected. The frequency of the homozygous extensive metabolizer phenotype was 32.96% (59/179), the heterozygous extensive metabolizer phenotype was 53.07% (95/179) and the poor metabolizers was 13.96% (25/179). Among the CAD patients in Chongqing, there is no significant statistical difference between these CYP2C19 genotypes and reports in other studies Conclusion: The CYP2C9 gene existed genetic polymorphism in CAD patients in Chongqing, and the distributions of allele frequency and metabolic phenotype frequency are similar to other districts in China.

Observational Study of Associations between Voriconazole Therapeutic Drug Monitoring, Toxicity, and Outcome in Liver Transplant Patients.

The aim of this study was to investigate the variability of the voriconazole plasma level and its relationships with clinical outcomes and adverse events among liver transplant recipients to optimize the efficacy and safety of their treatment. Liver transplant recipients treated with voriconazole were included, and voriconazole trough levels were quantified by a validated high-performance liquid chromatography method. Cytochrome P450 genotypes for CYP2C19 were evaluated in allograft liver tissues. A total of 832 voriconazole trough levels from 104 patients were measured. Proven, probable, and possible invasive fungal infections were reported for 8/104 (7.7%), 42/104 (40.4%), and 54/104 (51.9%) patients, respectively. Receiver operating characteristic (ROC) curve analysis indicated that trough concentrations of ≥1.3 μg/ml minimized the incidence of treatment failure (95% confidence interval [CI], 0.68 to 0.91 μg/ml) (P < 0.001) and that those of <5.3 μg/ml minimized the incidence of any adverse events (95% CI, 0.83 to 0.97 μg/ml) (P < 0.001). Voriconazole trough levels were significantly higher for heterozygous extensive metabolizers, poor metabolizers, and individuals receiving coadministration with proton pump inhibitors. For ultrarapid metabolizers, oral administration of voriconazole, and concomitant use of glucocorticoids, voriconazole blood concentrations were significantly reduced. Furthermore, there was no statistically significant association of patient age, weight, or gender or coadministration of tacrolimus and cyclosporine with the voriconazole trough level. In conclusion, the results of our analysis indicate large inter- and intraindividual variabilities of voriconazole concentrations in liver transplant recipients. Voriconazole trough concentrations of ≥1.3 μg/ml and <5.3 μg/ml are optimal for treatment and for minimization of adverse events. Optimization of drug efficacy and safety requires the use of rational doses for voriconazole therapy.

Notable Drug–Drug Interaction Between Etizolam and Itraconazole in Poor Metabolizers of Cytochrome P450 2C19

In this study, impact of a polymorphism of CYP2C19 on drug-drug interaction (DDI) was examined for etizolam. The effect of itraconazole (a strong CYP3A inhibitor) on the pharmacokinetics of etizolam (a substrate of CYP2C19 and CYP3A) was assessed in both extensive metabolizers (EMs) and poor metabolizers (PMs) of CYP2C19. Sixteen participants (8 EMs and 8 PMs) received a single oral dose of etizolam (0.25mg) on day 1. The participants ingested itraconazole (200mg twice a day) on days 2-5. On day 5, participants received an oral dose of etizolam (0.25mg) again. Before coadministration of itraconazole (day 1), the area under the time-plasma concentration curve from time zero to infinity (AUC∞ ) of etizolam was higher in PMs than in EMs (2.65-fold, P < .01). Coadministration of itraconazole increased the AUC∞ of etizolam 1.66-fold and 2.34-fold in EMs and PMs, respectively (day 5). Consequently, AUC∞ was 6.18-fold higher in PMs with itraconazole than that in EMs without itraconazole. The increase by itraconazole was larger in PMs (P < .01). In heterozygous EMs (hEMs), AUC∞ was simulated to be 2.56-fold higher with itraconazole than that in EMs without itraconazole. We found that in vitro measurements of fraction metabolized (fm ) using the liver microsome prepared from PM donors would be helpful to predict polymorphism-dependent DDIs. These results suggest that the PMs and hEMs of a polymorphic CYP would be at higher risk of DDIs relative to EMs for drugs metabolized by both polymorphic and nonpolymorphic CYPs such as etizolam.

Influence of CYP2C19 on Helicobacter pylori eradication in Brazilian patients with functional dyspepsia.

The aim of this study was to examine the effect of polymorphisms in the cytochrome P450 (CYP) 2C19 gene (CYP2C19) on the Helicobacter pylori eradication rate in Brazilian patients with functional dyspepsia. Adults diagnosed with functional dyspepsia based on the ROME III criteria and infected with H. pylori were recruited to this study. The patients were subjected to gastrointestinal endoscopy and the H. pylori status was defined when both urease test and histopathology results were negative or positive. The patients were treated with proton pump inhibitor-based triple therapy (omeprazole, amoxicillin, and clarithromycin). CYP2C19*2 and CYP2C19*3 were genotyped by polymerase chain reaction-restriction fragment length polymorphism. One hundred and forty-eight patients (81.8% women) with a mean (± SD) age of 46.1 (12.2) years were included in this study. Based on the CYP2C19 genotypes, the patients were classified as homozygous extensive metabolizer (HomEM; 67.6%), heterozygous extensive metabolizer (HetEM; 26.3%), or poor metabolizer (PM; 6.1%). The H. pylori eradication rates in patients with HomEM, HetEM, and PM were 85.0, 89.7, and 100.0% (P = 0.376), respectively. The included study population comprised a high frequency of patients carrying the HomEM genotype. Although the genotypes of CYP2C19 variants were not statistically significant, the results of this study suggest a possible effect of the PM genotype on the efficacy of H. pylori eradication.

Impact of genetic variability in CYP2D6, CYP3A5, and ABCB1 on serum concentrations of quetiapine and N-desalkylquetiapine in psychiatric patients.

To investigate the impact of genetic variability in CYP2D6, CYP3A5, and ABCB1 on steady-state serum concentrations of quetiapine and the active metabolite, N-desalkylquetiapine, in psychiatric patients. Measured serum concentrations of quetiapine and N-desalkylquetiapine from patients with biobanked DNA samples were included retrospectively from a routine therapeutic drug monitoring database. The impact of CYP2D6, CYP3A5, and ABCB1 (345C>T) genotypes on dose-adjusted serum concentrations (C/D ratios) of quetiapine and N-desalkylquetiapine was investigated by multivariate mixed model analysis. In total, 289 patients with 633 serum measurements were included. In the multivariate analysis, mean C/D ratio of N-desalkylquetiapine was estimated to be 33% and 22% higher in inherent CYP2D6 poor metabolizers (P = 0.03) and heterozygous extensive metabolizers (P < 0.001), respectively, compared with inherent extensive metabolizers. The ABCB1 3435C>T polymorphism and CYP3A5 genotype had no significant influence on either of the substances in the present material. Genetic variability in CYP2D6 contributes to the interindividual variability in steady-state serum concentrations of N-desalkylquetiapine. Although the metabolite exhibits relevant pharmacological activity, the quantitative effect of CYP2D6 genotype on serum concentration of N-desalkylquetiapine is probably of limited clinical relevance for quetiapine treatment.

Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups.

The aim of the present study was to investigate the effect of age on venlafaxine and escitalopram serum concentrations in various cytochrome P450 (CYP) 2D6 and CYP2C19 genotype subgroups. Serum concentration measurements from CYP-genotyped patients treated with venlafaxine (n = 255) or escitalopram (n = 541) were collected retrospectively from a therapeutic drug monitoring database. Patients were divided into three CYP2D6 (venlafaxine) or CYP2C19 (escitalopram) phenotype subgroups according to inherited genotype, i.e., poor metabolizers (PMs), heterozygous extensive metabolizers (HEMs), and extensive metabolizers (EMs), and subsequently distributed into three age groups, i.e., <40 (control), 40-65, and >65 years. The effect of age on dose-adjusted serum concentrations (i.e., nmol/L/mg/day) of venlafaxine and escitalopram in each of the phenotype subgroups was evaluated by separate multivariate mixed model analyses. In CYP2D6 PMs, the mean dose-adjusted serum concentration of venlafaxine was 8-fold higher in patients >65 years compared with those <40 years (p < 0.001). In comparison, the respective age-related differences in mean dose-adjusted serum concentrations of venlafaxine were much less pronounced in CYP2D6 HEMs and EMs (<2-fold differences between age groups). A similar genotype-related effect of age was not observed for escitalopram (<1.5-fold age differences in all CYP2C19 subgroups). This study suggests that the effect of age on serum concentration of venlafaxine is dependent on CYP genotype, in contrast to escitalopram. Thus, to prevent potential side effects, it might be particularly relevant to consider CYP2D6 genotyping prior to initiation of venlafaxine treatment in older patients.

Analysis of the CYP2C19 genetic polymorphism in Han and Uyghur patients with cardiovascular and cerebrovascular diseases in the Kashi area of Xinjiang.

BackgroundThe aim of this study was to analyze the CYP2C19 genetic polymorphism among Han and Uyghur patients with cardiovascular and cerebrovascular diseases in the Kashi area of Xinjiang.Material/MethodsWe enrolled 1020 patients with cardiovascular and cerebrovascular diseases, including 220 Han subjects and 800 Uyghur subjects. We used the gene chip method to detect polymorphisms in CYP2C19. The allele frequencies of CYP2C19 and the metabolic phenotype frequencies were then compared between the 2 ethnic groups.ResultsThe frequency of CYP2C19 *1 was 0.6454 in Han subjects and 0.7869 in Uyghur subjects, and the difference was statistically significant (P<0.05). The frequency of CYP2C19 *2 was 0.3273 in Han subjects and 0.1837 in Uyghur subjects (P<0.05). The frequency of the homozygous extensive metabolizer phenotype was 42.72% and 62.13% in Han and Uyghur subjects, respectively (P<0.01). The frequency of the heterozygous extensive metabolizer phenotype was 43.64% and 33.13% in Han and Uyghur subjects, respectively (P<0.01). The frequency of poor metabolizers in Han and Uyghur subjects was 13.64% and 4.76%, respectively (P<0.01).ConclusionsAmong patients with cardiovascular and cerebrovascular diseases located in the Kashgar Prefecture of Xinjiang, there is a differential distribution of CYP2C19 genotypes between the Han and Uyghur populations. Uyghur patients showed higher frequencies of extensive metabolizer genotypes than Han patients, while Han patients showed higher frequencies of poor metabolizer genotypes than Uyghur patients.

Evidence of Sex-related Differences in Cytochrome P450 2C19 and 3A4 Mediated Metabolism of Omeprazole: Observations in an Understudied Population in South-East Anatolia in Turkey

Sex-dependent and population differences in the activities of cytochrome P450 enzymes affect the metabolism of many xenobiotics, including drugs. The proton pump inhibitor omeprazole is widely prescribed in many countries that call for population studies of its disposition. Omeprazole is metabolized by CYP2C19 and CYP3A4, resulting in the formation of 5-hydroxyomeprazole and omeprazole sulfone, respectively. This study examined the sex-differences in CYP2C19-, and CYP3A4-mediated metabolism of omeprazole in an understudied population in Turkey. Data were obtained from 107 healthy unrelated subjects (51 females and 56 males; heterozygous and homozygous extensive metabolizers (EMs) in regard to CYP2C19) from a recent study on the relationship between CYP2C19 genotype and phenotype, using a single oral dose of 60 mg R,S-omeprazole. The differences in plasma concentrations of racemic omeprazole, its R- and S-enantiomers, 5-hydroxyomeprazole, and omeprazole sulfone as well as the metabolic ratios of omeprazole and its enantiomers were compared between females and males. We also examined the parameters mentioned above in homozygous EM (CYP2C19*1/*1) subjects (n=90). No significant differences of metabolic ratios (MRs) (omeprazole/5-hydroxyomeprazole (O/OHO), omeprazole/omeprazole sulfone (O/OS), omeprazole plus 5-hydroxyomeprazole/ omeprazole sulfone (O+OHO/OS), omeprazole plus omeprazole sulfone/5-hydroxyomeprazole (O+OS/OHO), and the same ratios for its S-, and R- enantiomers) were found between females and males in the homozygous EM group, except a trend for difference of the O+OS/OHO (P=0.061), RO+OS/OHO (P=0.047) and SO+OS/OHO (P=0.072) MRs, which was higher in females. In the heterozygous plus homozygous EMs with regard to CYP2C19, the MR of O+OS/OHO (P=0.059) was borderline higher in females, while the O+OHO/OS (P=0.009) MR was higher in males. Similar results were found for MRs of R-, and S-omeprazole (RO+OS/OHO, P=0.040; SO+OS/OHO P=0.018; RO+OHO/OS, P=0.005; SO+OHO/OS, P=0.007). There are sex-related differences in the MRs of omeprazole and its R-, and S- enantiomers, also suggesting that females have a higher CYP3A4, but a slightly lower CYP2C19 activity compared to males in healthy Turkish subjects.

Effects of CYP2C19 Loss-of-Function Variants on the Eradication of H. pylori Infection in Patients Treated with Proton Pump Inhibitor-Based Triple Therapy Regimens: A Meta-Analysis of Randomized Clinical Trials

BackgroundThere are inconsistent conclusions about whether CYP2C19 variants could affect H. pylori eradication rate in patients treated with the proton pump inhibitor (PPI)-based therapy. We therefore performed a meta-analysis of randomized clinical trials (RCTs) to re-evaluate the impact of CYP2C19 variants on PPI-based triple therapy for the above indication.MethodsAll relevant RCTs in the PubMed, Cochrane Library, EMBASE, Web of Science and two Chinese databases (up to February 2013) were systematically searched, and a pooled analysis was performed with the odds ratio (OR) and 95% confidence interval (CI) by the STATA software.ResultsSixteen RCT datasets derived from 3680 patients were included. There was no significant heterogeneity across the data available in this meta-analysis. There were significant differences in that rate between homozygous (HomEMs) and heterozygous (HetEMs) extensive metabolizers (OR 0.724; 95% CI 0.594–0.881), between HomEMs and poor metabolizers (PM) (OR 0.507; 95%CI 0.379–0.679), or between HetEMs and PMs (OR 0.688; 95%CI 0.515–0.920), regardless of the PPI being taken. Furthermore, sub-analysis of individual PPIs was carried out to explore the difference across all the PPIs used. A significantly low rate was seen in HomEMs vs. HetEMs taking either omeprazole (OR 0.329; 95%CI 0.195–0.553) or lansoprazole (OR 0.692; 95%CI 0.485–0.988), and also in HomEMs vs. PMs for omeprazole (OR 0.232; 95%CI 0.105–0.515) or lansoprazole (OR 0.441; 95%CI 0.252–0.771). However, there was no significant difference between HetEMs and PMs taking either one. No significant differences were observed for rabeprazole or esomeprazole across the CYP2C19 genotypes of interest.ConclusionsCarriage of CYP2C19 loss-of-function variants is associated with increased H. pylori eradication rate in patients taking PPI-based triple therapies when omeprazole or lansoprazole is chosen. However, there is no a class effect after use of rabeprazole or esomeprazole.

Biological interactions of CYP2C19 genotypes with CYP3A4*18, CYP3A5*3, and MDR1-3435 in living donor liver transplantation recipients

BackgroundPolymorphisms in CYP2C19 are related to the metabolic oxidation of drugs to varying degrees. The CYP3A4*18, CYP3A5*3, and MDR1-3435 variant alleles are very important, particularly in tacrolimus metabolism in organ transplant rejection.AimThe aim of this study is o explore possible interactions among different CYP2C19 genotypes, namely, between homozygous extensive metabolizers (HomEM), heterozygous extensive metabolizers (HetEM), and poor metabolizers (PM), and the CYP3A4*18, CYP3A5*3, and MDR1-3435 variants in living donors and patients who received a living donor liver transplant (LDLT).MethodsThis prospective study enrolled 133 living donors and 133 corresponding recipients. On the basis of the HomEM, HetEM, and PM CYP2C19 genotypes, the distributions of CYP3A4*18 (exon 10; T878C), CYP3A5*3 (intron 3; A6986G), and MDR1-3435 (exon 26; C3435T) genotypes were analyzed for single nucleotide polymorphisms among donors and recipients.ResultsAmong 102 HomEM genotypes, including 56 donors and 46 recipients, 91.2% of individuals harbored the T/T genotype of CYP3A4*18; 53.9% possessed G/G, and 34.3% had A/G genotypes of CYP3A5*3; and 38.2% had C/C and 50.0% had C/T genotypes at MDR1-3435. Among 130 HetEM genotypes, including 58 donors and 72 recipients, 97.7% of individuals possessed T/T genotype at CYP3A4*18; 50.0% harbored G/G and 41.5% had A/G genotypes at CYP3A5*3; and 40.0% had C/C and 49.2% had C/T genotypes at MDR1-3435. In 34 PMs, including 19 donors and 15 recipients, 88.2% had T/T genotypes at CYP3A4*18; 41.2% had G/G and 58.8% had A/G genotypes at CYP3A5*3; and 47.1% possessed C/C and 47.1% had C/T genotypes at MDR1-3435. On the basis of the CYP2C19 genotypes, no statistically significant distribution of genotypes were observed between donors and recipients for all genotypes of CYP3A4*18, CYP3A5*3, and MDR1-3435 (P >0.05).ConclusionsIn conclusion, the CYP2C19 genotypes do not affect the expression of CYP3A4*18, CYP3A5*3, or MDR1-3435 variants, which are independently distributed among donors and recipients during LDLT.

Clinical Impact of Cytochrome P450 2C19 Genotype on the Treatment of Invasive Aspergillosis under Routine Therapeutic Drug Monitoring of Voriconazole in a Korean Population

BackgroundGenetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However, the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established.Materials and MethodsIn this prospective observational study, we analyzed all consecutive adult patients with hematologic diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1-5.5 mg/L.ResultsA total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively).ConclusionsWhile none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large-scale multicenter studies using clinical data from homogeneous populations are required.

The use of the 13C-dextromethorphan breath test for phenotyping CYP2D6 in breast cancer patients using tamoxifen: association with CYP2D6 genotype and serum endoxifen levels

Adjuvant therapy with tamoxifen significantly reduces breast cancer recurrence and mortality in estrogen receptor positive disease. CYP2D6 is the main enzyme involved in the activation of the prodrug tamoxifen into the anti-estrogen endoxifen. Endoxifen is thought to be a main determinant for clinical efficacy in breast cancer patients using tamoxifen. As the large interindividual variation in endoxifen levels is only partly explained by CYP2D6 genotype, we explored the use of the (13)C-dextromethorphan breath test (DM-BT) for phenotyping CYP2D6 and to predict serum steady-state endoxifen levels as a marker for clinical outcome in breast cancer patients using tamoxifen. In 65 patients with early breast cancer using tamoxifen, CYP2D6 phenotype was assessed by DM-BT. CYP2D6 genotype using Amplichip and serum steady-state levels of endoxifen were determined. Genotype was translated into the gene activity score and into ultrarapid, extensive, heterozygous extensive, intermediate or poor metabolizer CYP2D6 predicted phenotype. CYP2D6 phenotype determined by the DM-BT explained variation in serum steady-state endoxifen levels for 47.5% (R(2) = 0.475, p < 0.001). Positive and negative predictive values for a recently suggested threshold serum level of endoxifen (5.97 ng/mL) for breast cancer recurrence rate were 100 and 90%, respectively, for both CYP2D6 phenotype by DM-BT (delta-over-baseline at t = 50 min (DOB(50)) values of 0.7-0.9) and genotype (CYP2D6 gene activity score of 1.0). DM-BT might be, along with CYP2D6 genotyping, of value in selection of individualized endocrine therapy in patients with early breast cancer, especially when concomitant use of CYP2D6 inhibiting medication alters the phenotype.

CYP2D6 genotype affects age-related decline in flecainide clearance

To investigate the association between age-related decline in flecainide clearance and CYP2D6 genotype, we conducted a population pharmacokinetic analysis of flecainide using routine therapeutic drug monitoring data. Population pharmacokinetic analysis was performed on retrospective data from 163 genotyped patients treated with oral flecainide for supraventricular tachyarrhythmias. The CYP2D6 genotype was categorized as CYP2D6 homozygous extensive metabolizers (hom-EMs; n=57), heterozygous extensive metabolizers (het-EMs; n=79), and intermediate metabolizers and poor metabolizers (IMs/PMs; n=27). Population pharmacokinetic analysis revealed that estimated glomerular filtration rate, body weight, female sex, and aging were important factors for estimating flecainide clearance. The metabolic clearance was decreased age dependently in a curvilinear fashion, where the lower clearance was observed in greater than 60 years for het-EMs and greater than 55 years for IMs/PMs. The reduction in metabolic clearance in elderly (70 years) patients compared with middle-aged (52 years) patients was different among the CYP2D6 genotype groups: 22.1 and 49.5% in CYP2D6 het-EMs and IMs/PMs, respectively, and no change in hom-EMs. A 11.4% reduction in estimated glomerular filtration rate in elderly patients compared with middle-aged patients corresponded to 6.1% decline in flecainide clearance. Overall, the age-related decline in flecainide clearance was 6.1% in hom-EMs, 16.3% in het-EMs, and 28.9% in IMs/PMs groups. This study suggests that CYP2D6 genotype is a determinant factor of age-related decline in flecainide clearance.

The Influence of Omeprazole on Platelet Inhibition of Clopidogrel in Various CYP2C19 Mutant Alleles

Currently, concerns of clopidogrel and proton pump inhibitors (especially omeprazole) interaction are raised, because they are both metabolized by CYP2C19. What is more, omeprazole can also inhibit the activity of CYP2C19. The study was to compare the influence of omeprazole on platelet inhibition of clopidogrel in various CYP2C19 mutant alleles. One hundred forty-two consecutive patients undergoing elective coronary stenting received aspirin and clopidogrel, and were randomized to omeprazole or the placebo. Enrolled patients were analyzed for adenosine diphosphate-induced platelet aggregation (ADP-Ag), and CYP2C19*2 and CYP2C19*3 were identified by polymerase chain reaction-restriction fragment length polymorphism. Of the patients included, 47 (33.1%) belonged to homozygous extensive metabolizers (homEMs) (CYP2C19*1/*1), 70 (49.3%) belonged to heterozygous extensive metabolizers (hetEMs) (*1/*2 or *1/*3), and 25 (17.6%) belonged to poor metabolizers (PMs) (*2/*3 or *2/*2). ADP-Ag had a significant difference among the three genotypic groups (p<0.01). Moreover, the present study revealed that the degree of the interaction between clopidogrel and omeprazole was not homogeneous within the various genotypes of CYP2C19. The difference of ADP-Ag between the patients with and without omeprazole was significantly largest in homEMs (45.7%±14.2% vs. 35.5%±16.0%, p<0.05). However, any significant difference of ADP-Ag between the patients with and without omeprazole was not observed in other two genotypic groups (hetEMs and PMs, p>0.05). In conclusion, concomitant therapy with omeprazole appears to reduce the antiplatelet effect of clopidogrel most significantly in homEMs of CYP2C19.