Homozygous 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.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

Pediatric AIDS-Therapeutic Successes Built on a Foundation of Pediatric Clinical Pharmacology with Pharmacokinetic-Pharmacodynamic Modeling.

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.

Impact of CYP2D6 Functional Allelic Variations on Phenoconversion and Drug-Drug Interactions.

We investigated whether CYP2D6 extensive metabolizers carrying a nonfunctional allele are at higher risk of phenoconversion to poor metabolizers in the presence of CYP2D6 inhibitors. Seventeen homozygous carriers of two fully-functional alleles and 17 heterozygous carriers of one fully-functional and one nonfunctional allele participated in this trial. Dextromethorphan 5 mg and tramadol 10 mg were given at each of the three study sessions. CYP2D6 was inhibited by duloxetine 60 mg (session 2) and paroxetine 20 mg (session 3). A higher rate of phenoconversion to intermediate metabolizers with duloxetine (71% vs. 25%, P = 0.009) and to poor metabolizers with paroxetine (94% vs. 56%, P = 0.011) was observed in heterozygous than homozygous extensive metabolizers. The magnitude of drug-drug interaction between dextromethorphan and paroxetine was higher in homozygous than in heterozygous subjects (14.6 vs. 8.5, P < 0.028). Our study suggests that genetic extensive metabolizers may not represent a homogenous population and that available genetic data should be considered when addressing drug-drug interactions in clinical practice.

Effects of cytochrome P450 3A4 and non-genetic factors on initial voriconazole serum trough concentrations in hematological patients with different cytochrome P450 2C19 genotypes

1. Polymorphisms of cytochrome P450 2C19 (CYP2C19) is an important factor contributing to variability of voriconazole pharmacokinetics. Polymorphisms of CYP3A4, CYP3A5, CYP2C9 and non-genetic factors such as age, gender, body mass index (BMI), transaminase levels, concomitant medications might also affect voriconazole initial steady serum trough concentration (VICmin) in haematological patients, but the effects were not clear.2. Eighteen single-nucleotide polymorphisms in CYP2C19, CYP3A4, CYP3A5, CYP2C9 were genotyped. Patients were stratified into two groups according to CYP2C19 genotype. Group 1 were patients with CYP2C19*2 or CYP2C19*3, and Group 2 were homozygous extensive metabolizers. The effects were studied in different groups. VICmin was adjusted on daily dose (VICmin/D) for overcoming effect of dose.3. A total of 106 blood samples from 86 patients were included. In final optimal scaling regression models, polymorphisms of rs4646437 (CYP3A4), age, BMI was identified to be factors of VICmin/D in Group 1 (R2 = .255, p < .001). Only age was confirmed as a factor of VICmin/D in Group 2 (R2 = 0.144, p = .021).4. Besides polymorphisms of CYP2C19, in individualized medication of voriconazole in haematological patients, polymorphisms of CYP3A4, and non-genetic factors as BMI, age should also be taken into account, especially for individuals with CYP2C19*2 or CYP2C19*3.

Effects of polymorphisms in CYP2D6 and ABC transporters and side effects induced by gefitinib on the pharmacokinetics of the gefitinib metabolite, O-desmethyl gefitinib.

We investigated the effects of polymorphisms in CYP2D6, ABCB1, and ABCG2 and the side effects induced by gefitinib on the pharmacokinetics of O-desmethyl gefitinib, the active metabolite of gefitinib. On day 14 after beginning therapy with gefitinib, plasma concentrations of gefitinib and O-desmethyl gefitinib were measured. Patients were grouped into three groups according to their combination of CYP2D6 alleles: homozygous extensive metabolisers (EMs; *1/*1, *1/*2, and *2/*2; n=13), heterozygous EMs (*1/*5, *2/*5, *1/*10, and *2/*10; n=18), and intermediate metabolisers (IMs; *5/*10 and *10/*10; n=5). The median AUC0-24 of O-desmethyl gefitinib in CYP2D6 IMs was 1460ngh/mL, whereas that in homozygous EMs was 12,523ngh/mL (P=0.021 in univariate analysis). The median AUC ratio of O-desmethyl gefitinib to gefitinib differed among homozygous EMs, heterozygous EMs, and IMs at a ratio of 1.41:0.86:0.24 (P=0.030). On the other hand, there were no significant differences in the AUC0-24 of O-desmethyl gefitinib between ABCB1 and ABCG2 genotypes. In a multivariate analysis, CYP2D6 homozygous EMs (P=0.012) were predictive for a higher AUC0-24 of O-desmethyl gefitinib. The side effects of diarrhoea, skin rash, and hepatotoxicity induced by gefitinib were unrelated to the AUC0-24 of O-desmethyl gefitinib. CYP2D6 polymorphisms were associated with the formation of O-desmethyl gefitinib from gefitinib. In CYP2D6 homozygous EMs, the plasma concentrations of O-desmethyl gefitinib were higher over 24h after taking gefitinib than those of the parent compound; however, side effects induced by gefitinib were unrelated to O-desmethyl gefitinib exposure.

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.

Effects of CYP2C19 and P450 Oxidoreductase Polymorphisms on the Population Pharmacokinetics of Clobazam and N-Desmethylclobazam in Japanese Patients With Epilepsy

Clobazam (CLB) is a 1,5-benzodiazepine with antiepileptic properties. More than 70% of administered CLB is dealkylated to yield N-desmethylclobazam (N-CLB), a pharmacologically active metabolite, by cytochrome P450 (CYP) 3A4 and CYP2C19. The subsequent inactivation of N-CLB is primarily catalyzed by CYP2C19. Meanwhile, P450 oxidoreductase (POR) is the obligatory electron donor to all microsomal CYP enzymes. The aim of this study was to evaluate the impact of the CYP2C19 and POR genotypes on the pharmacokinetic parameters of CLB and N-CLB. This retrospective study included 85 Japanese patients with epilepsy who were treated with CLB. CYP2C19*2, *3, and P450 oxidoreductase (POR) *28 (rs1057868C>T) polymorphisms were evaluated. A total of 128 steady-state concentrations for both CLB and N-CLB were collected from the patients. A nonlinear mixed-effects model identified the pharmacokinetics of CLB and N-CLB; the covariates included CYP2C19 and POR genotypes, weight, gender, daily CLB dose, and coadministered antiepileptic drugs. Among the 85 patients, the allele frequencies of CYP2C19*2, CYP2C19*3, and POR*28 were 27.6%, 12.9%, and 41.2%, respectively. A one-compartment model with first-order absorption and/or elimination showed that the clearance of CLB and N-CLB was significantly lower by 18.1% and 84.9%, respectively, in the CYP2C19 poor metabolizers compared with the homozygous extensive metabolizers. The CLB clearance was 44% higher in subjects homozygous for the POR*28 T allele than in those homozygous for the POR*28 C allele, although the genotypes did not affect the N-CLB clearance. The concomitant use of phenobarbital, phenytoin, and zonisamide significantly affected the CLB clearance, whereas that of carbamazepine, phenytoin, and valproic acid affected the N-CLB clearance. The weight also significantly influenced the CLB clearance and volume of distribution of both CLB and N-CLB. Our results showed that the CYP2C19 and/or POR genotypes have an impact on the CLB and/or N-CLB clearance. These results suggest that determining the CYP2C19 and/or POR genotypes is helpful for obtaining appropriate serum CLB and N-CLB concentrations and preventing an overdose when starting CLB therapy.

Brivaracetam Single and Multiple Rising Oral Dose Study in Healthy Japanese Participants: Influence of CYP2C19 Genotype

Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in phase 3 clinical development for epilepsy. A phase 1, single-center, randomized, double-blind, placebo-controlled, single (2.5-100 mg) and multiple (2.5-50 mg twice daily) rising oral dose study (N01209) was conducted to assess the adverse event profile and pharmacokinetics of brivaracetam in healthy Japanese men, and the influence of the cytochrome P450 (CYP) 2C19 genotype. Plasma and urine were collected serially for analysis of brivaracetam and its three main metabolites: acid, hydroxy and hydroxy acid. Overall, 79/80 randomized participants completed the study. Brivaracetam was generally well tolerated. After single- and multiple-dose administration, brivaracetam was rapidly absorbed, with dose-proportional pharmacokinetics over the dose ranges tested. Steady state was reached after 2 days of repeated dosing. Brivaracetam clearance (averaged across the five single dose levels) was reduced from 0.99 mL/min/kg in homozygous extensive metabolizers (EM; n = 10) to 0.81 mL/min/kg (-18%) in heterozygous EM (n = 17) and 0.70 mL/min/kg (-29%) in poor metabolizers (PM; n = 9). Exposure and urinary excretion of hydroxy metabolite were reduced 10-fold in PM participants, compared with EM participants. Results suggest that brivaracetam is hydroxylated by CYP2C19, but this pathway is minor compared with hydrolysis to the acid metabolite.

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.

Serum concentrations of tamoxifen and its metabolites increase with age during steady-state treatment

It has been suggested that the concentrations of tamoxifen and its demethylated metabolites increase with age. We measured the serum concentrations of the active tamoxifen metabolites, 4OHtamoxifen (4OHtam), 4-hydroxy-N-desmethyltamoxifen (4OHNDtam, Endoxifen), tamoxifen and its demethylated metabolites. Their relations to age were examined. One hundred fifty-one estrogen receptor and/or progesterone receptor positive breast cancer patients were included. Their median (range) age was 57 (32–85) years. Due to the long half-life of tamoxifen, only patients treated with tamoxifen for at least 80 days were included in the study in order to insure that the patients had reached steady-state drug levels. Tamoxifen and its metabolites were measured by liquid chromatography-tandem mass spectrometry. Their serum concentrations were related to the age of the patients. To circumvent effects of cytochrome (CYP) 2D6 polymorphisms we also examined these correlations exclusively in homozygous extensive metabolizers. The concentrations of 4OHNDtam, tamoxifen, NDtam (N-desmethyltamoxifen), and NDDtam (N-desdimethyltamoxifen) were positively correlated to age (n = 151, p = 0.017, 0.045, 0.011, and 0.001 respectively). When exclusively studying the CYP2D6 homozygous extensive metabolizers (n = 86) the correlation between 4OHNDtam and age increased (p = 0.008). Up to tenfold inter-patient variation in the serum concentrations was observed. The median (inter-patient range) concentration of 4OHNDtam in the age groups 30–49, 50–69, and >69 years were 65 (24–89), 116 (25–141), and 159 (26–185) ng/ml, respectively. We conclude that the serum concentrations of 4OHNDtam (endoxifen), tamoxifen, and its demethylated metabolites increase with age during steady-state tamoxifen treatment. This may represent an additional explanation why studies on the effects of CYP2D6 polymorphisms on outcome in tamoxifen-treated breast cancer patients have been inconsistent. The observed high inter-patient range in serum concentrations of tamoxifen and its metabolites, especially in the highest age group, suggest that use of therapeutic monitoring of tamoxifen and its metabolites is warranted.

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.

Association of CYP2D6 and CYP2C19 polymorphisms and disease-free survival of Thai post-menopausal breast cancer patients who received adjuvant tamoxifen

PurposeTo investigate the impact of CYP2D6 and CYP2C19 polymorphisms in predicting tamoxifen efficacy and clinical outcomes in Thai breast cancer patients.MethodsPolymorphisms of CYP2D6 and CYP2C19 were genotyped by the AmpliChip™ CYP450 Test (Roche Molecular Diagnostics, Branchburg, NJ, USA) for 57 patients, who were matched as recurrent versus non-recurrent breast cancers (n = 33 versus n = 24, respectively, with a 5-year follow-up).ResultsBased on the genotype data, five CYP2D6 predicted phenotype groups were identified in this study including homozygous extensive metabolizer (13 of 57, 22.80%), extensive/intermediate metabolizer (23 of 57, 40.40%), extensive/poor metabolizer (3 of 57, 5.30%), homozygous intermediate metabolizer (14 of 57, 24.50%), and intermediate/poor metabolizer (4 of 57, 7.00%), and three CYP2C19 genotype groups including homozygous extensive metabolizer (27 of 57, 47.40%), extensive/intermediate metabolizer (27 of 57, 47.40%), and homozygous poor metabolizer (3 of 57, 5.30%). The CYP2D6 variant alleles were *10 (52 of 114, 45.60%), *5 (5 of 114, 4.40%), *41 (2 of 114, 1.80%), *4 (1 of 114, 0.90%), and *36 (1 of 114, 0.90%); the CYP2C19 variant alleles were *2 (27 of 114, 23.70%) and *3 (6 of 114, 5.30%). Kaplan–Meier estimates showed significantly shorter disease-free survival in patients with homozygous TT when compared to those with heterozygous CT or homozygous CC at nucleotides 100C>T and 1039C>T (CYP2D6*10) post-menopausal (log-rank test; P = 0.046). They also had increased risk of recurrence, but no statistically significant association was observed (hazard ratio 3.48; 95% confidence interval 0.86–14.07; P = 0.080).ConclusionThe CYP2D6 and CYP2C19 polymorphisms were not involved in tamoxifen efficacy. However, in the subgroup of post-menopausal women, the polymorphisms in CYP2D6 and CYP2C19 might be useful in predicting tamoxifen efficacy and clinical outcomes in breast cancer patients receiving adjuvant tamoxifen treatment. As the number of breast cancer patients was relatively small in this study, results should be confirmed in a larger group of prospective patients.

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.