Heterozygous EMs Research Articles

Microarray-Based Detection and Clinical Evaluation for Helicobacter pylori Resistance to Clarithromycin or Levofloxacin and the Genotype of CYP2C19 in 1083 Patients.

Background. Helicobacter pylori (H. pylori) is one of the most frequent and persistent bacterial infections that affect nearly half of the world's population. Antibiotic resistance is a constantly evolving process and local surveillance of antibiotic resistance is warranted to guide clinicians in their choice of therapy. The aim of this study was to establish a microarray-based detection to identify H. pylori infection, clarithromycin and levofloxacin susceptibility, and CYP2C19 genetic polymorphism and guide to potential choice of proton pump inhibitor (PPI), antibiotic administration for tailored H. pylori eradication therapy. Methods. By analyzing the sequence of human genomic CYP2C19⁎2 and CYP2C19⁎3 and mutations within the 23S rRNA and gyrA gene regions conferring clarithromycin and levofloxacin resistance, respectively, we developed a microarray for individual therapy detection of H. pylori infection. Plasmids were established as positive or limit of detection (LOD) reference materials. The specificity and sensitivity of the microarray had been performed. And a total of 1083 gastric biopsy samples were tested and the Kappa value had been calculated between the array and Sanger sequencing. We also analyzed the resistance to clarithromycin and levofloxacin in China, as well as the CYP2C19 polymorphisms. Results. The LOD of detecting H. pylori was 103 CFU/mL and human genome DNA was 2 ng/μL. The detection results of 1083 gastric biopsy samples showed that 691 (63.80%) were H. pylori positive, of which 266 (38.49%) were resistant to clarithromycin, 192 (27.79%) were resistant to levofloxacin, and 61 (8.83%) were resistant to both of them. For the type of CYP2C19 polymorphism, 412 (38.04%) were homozygous fast type (HomEM), 574 (53%) were heterozygous EM (HetEM), and 97 (8.96%) were poor metabolizer (PM). Conclusions. The proposed microarray-based detection has high specificity, sensitivity, and reproducibility for detecting the resistance of clarithromycin or levofloxacin as well as CYP2C19 polymorphism, which may help to improve the clinical eradication rate of H. pylori.

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.

CYP2C19 polymorphism influences Helicobacter pylori eradication.

The known factors that have contributed to the decline of Helicobacter pylori (H. pylori) eradication rate include antibiotic resistance, poor compliance, high gastric acidity, high bacterial load, and cytochrome P450 2C19 (CYP2C19) polymorphism. Proton pump inhibitor (PPI) is important in the eradication regimen. The principal enzyme implicated in the metabolism of PPIs is CYP2C19. The effects of PPI depend on metabolic enzyme, cytochrome P450 enzymes, and CYP2C19 with genetic differences in the activity of this enzyme (the homozygous EM, heterozygous EM (HetEM), and poor metabolizer). The frequency of the CYP2C19 polymorphism is highly varied among different ethnic populations. The CYP2C19 genotype is a cardinal factor of H. pylori eradication in patients taking omeprazole- based or lansoprazole-based triple therapies. In contrast, the CYP2C19 polymorphism has no significant effect on the rabeprazole-based or esomeprazole-based triple therapies. The efficacy of levofloxacin-based rescue triple therapy might be also affected by the CYP2C19 polymorphism, but CYP2C19 genotypes did not show obvious impact on other levofloxacin-based rescue therapies. Choice of different PPIs and/or increasing doses of PPIs should be individualized based on the pharmacogenetics background of each patient and pharmacological profile of each drug. Other possible factors influencing gastric acid secretion (e.g., IL-1β- 511 polymorphism) would be also under consideration.

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.

The (R)-omeprazole hydroxylation index reflects CYP2C19 activity in healthy Japanese volunteers

Omeprazole has (R)- and (S)-enantiomers, which exhibit different pharmacokinetics (PK) among patients with cytochrome P450 (CYP) 2C19 genotype groups. The aim of this study was to investigate whether the 1-point, 4-h postdose (R)-omeprazole hydroxylation index (HI) of racemic omeprazole reflects the three CYP2C19 genotype groups in Japanese individuals. Ninety healthy Japanese individuals were enrolled and classified into the three different CYP2C19 genotype groups: homozygous extensive metabolizers (hmEMs; n = 34), heterozygous EMs (htEMs; n = 44), and poor metabolizers (PMs; n = 12). Blood samples were drawn 4 h after the intake of an oral dose of omeprazole 40 mg, and plasma levels of omeprazole and its metabolites were analyzed by high-performance liquid chromatography (HPLC) using a chiral column. Mean plasma concentrations of (R)- and (S)-omeprazole in PMs were significantly higher than those in hmEMs and htEMs, and similar results were obtained in the case of omeprazole sulfone. Additionally, there was a significant difference in plasma concentrations of (R)-5-hydroxyomeprazole among CYP2C19 genotype groups, whereas no significant differences were observed in that of (S)-5-hydroxyomeprazole. Similarly, (R)-omeprazole HI in hmEMs, htEMs, and PMs were 5.6, 3.1, and 0.3, respectively, which were significantly different, but no significant difference was present in the (S)-omeprazole HI. Our findings demonstrate that (R)-omeprazole HI correlated better with CYP2C19 genotype groups than racemic-omeprazole HI, and these results may be useful for classification among patients in CYP2C19 genotype groups prior to omeprazole treatment.

Effect of CYP2C19 Genetic Polymorphism on Pharmacokinetics and Pharmacodynamics and Pharmacodynamics of a New Proton Pump Inhibitor, Ilaprazole

It is well known that the CYP2C19 genetic polymorphism influences the pharmacokinetics and pharmacodynamics of proton pump inhibitors (PPIs), but no report has addressed the effects on ilaprazole, a newly developed PPI. To investigate the effects of the CYP2C19 genetic polymorphism on the disposition and pharmacodynamics of ilaprazole, multiple doses of once-daily 10 mg ilaprazole were repeatedly administered for 7 days to 27 healthy Korean participants, comprising 9 homozygous CYP2C19 extensive metabolizers (homo EMs), 10 heterozygous EMs (hetero EMs), and 8 homozygous poor metabolizers (PMs). The plasma concentration and pharmacodynamic response were measured in the last dose interval. Each genotype group was matched for gender and thus was composed of 4 male and 4 female participants when the analysis was conducted. The pharmacokinetic parameters estimated from the plasma concentrations of ilaprazole and its metabolite ilaprazole sulfone, the serum gastrin level, and the 24-hour intragastric pH were compared among the CYP2C19 genotype groups. No statistically significant differences in the maximum plasma concentration at steady state(C(ss,max)) and the area under the concentration-time curve from zero to 24 hours (AUC(τ)) of ilaprazole and ilaprazole sulfone were observed among the homo EM, hetero EM, and PM CYP2C19 genotypes. In addition, the mean 24-hour intragastric pH, the percentage of time at pH >4, and the AUC(τ) of serum gastrin showed no significant differences among the CYP2C19 genotype groups. The data suggests that the pharmacokinetics and pharmacodynamics of ilaprazole are not significantly influenced by the CYP2C19 genetic polymorphism in healthy participants.

Effect of the CYP2C19 genotype on the pharmacokinetics of icotinib in healthy male volunteers

Icotinib hydrochloride {4-[(3-ethynylphenyl)amino]-6,7-benzo-12-crown-4-quinazoline hydrochloride}, a novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), was designed for the treatment of non-small cell lung cancer (NSCLC). In the present study, we investigated the influence of the CYP2C19*2 and CYP2C19*3 alleles on the pharmacokinetics of icotinib in healthy Chinese volunteers. In a single-dose pharmacokinetic study, 12 healthy Chinese volunteers received an oral dose of 600mg of icotinib. Plasma was sampled for up to 72h post-dose, followed by quantification of icotinib by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS-MS). Five subjects genotyped as homozygous extensive metabolizers (CYP2C19*1/*1), 6 subjects genotyped as heterozygous extensive metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria. The mean icotinib AUC(0-∞) and C(max) (14.56 ±5.31h mg/L and 2.32 ± 0.49μg/mL) in homozygous EMs was 1.56 and 1.41-fold lower than that in heterozygous EMs (22.7 ± 6.11 and 3.28 ± 0.48, P = 0.046 and 0.047). The mean CL/F (44.18 ± 12.17L/h) in homozygous EMs was 1.55-fold higher than that in heterozygous EMs (28.42 ± 9.23L/h, P = 0.013). The data showed that the pharmacokinetics of icotinib differ significantly between homozygous EMs and heterozygous EMs in CYP2C19.

Hydroxylation of R(+)- and S(−)-Omeprazole after Racemic Dosing are Different among the CYP2C19 Genotypes

To elucidate the stereoselective pharmacokinetics of omeprazole enantiomers and their metabolites after racemic IV dosing because there is little information about the stereoselective metabolism of omeprazole in in vivo study. Seventeen subjects were classified into three CYP2C19 groups based on their genotypes: homozygous extensive metabolizers (hmEMs; n = 5), heterozygous EMs (htEMs; n = 7) and poor metabolizers (PMs; n = 5). After single IV administration of racemic omeprazole (20 mg), the mean area under the plasma concentration-time curve (AUC(0-∞)) of R(+)-omeprazole in PMs was significantly higher than that in hmEMs and htEMs, while that of S(-)-omeprazole was no significance among three genotypes because of a wide inter-individual variability. In addition, although the AUC(0-∞) of R(+)-5-hydroxyomeprazole were determined among three genotypes, the that of S(-)-5-hydroxyomeprazole was undetectable in the hmEMs and barely detectable in the htEMs. Conversly, the AUC(0-∞) of S(-)-5-hydroxyomeprazole was greater than that of R(+)-5-hydroxyomeprazole in the PMs. These data therefore suggest that, for EMs, the CYP2C19-mediated formation from R(+)-enantiomer is a 5-hydroxy-metabolite, while that from S(-)-enantiomer may be a minor metabolite. Thus, the in vivo disposition of S(-)- and R(+)-omeprazole after racemic dosing may be different among the CYP2C19 genotypes.

Dose–response relationships of rabeprazole 5, 10, 20, and 40 mg once daily on suppression of gastric acid secretion through the night in healthy Japanese individuals with different CYP2C19 genotypes

This study was designed to investigate the antisecretory activity of rabeprazole administered once daily in doses of 5, 10, 20, and 40 mg and different cytochrome P450 2C19 (CYP2C19) genotypes on gastric pH in healthy individuals. Additional objectives were delineating the nighttime from the daytime effect and determining the relationships between the pharmacokinetics and pharmacodynamics of rabeprazole. Eight individuals of each of the three genotypes of CYP2C19-homozygous extensive metabolizers (homo-EMs), heterozygous EMs (hetero-EMs), and poor metabolizers (PMs)-were recruited. Twenty-four individuals received a once-daily dose, with dosing interval 24 h of 5, 10, 20, or 40 mg rabeprazole for 5 days in a 4-period crossover fashion. Twenty-four-hour intragastric pH and plasma rabeprazole concentrations were determined on day 5. A dose-dependent increase in median pH and in pH 4 holding time was observed across all CYP2C19 genotypes. When rabeprazole was increased from 20 mg to 40 mg, the differences and 95% confidence intervals (CIs) of nighttime pH 4 holding time between 40 mg and 20 mg in homo-EMs, hetero-EMs, and PMs were 8.0% (-5.0% -21.0%), 28.7% (15.7% -41.6%), and 16.9% (3.9% -29.9%), respectively. The relationship between the area under the plasma concentration-time curve up to the last time point at which rabeprazole was quantifiable (AUC(0-t)) and the pH 4 holding time could be described using a sigmoid maximum effect (E(max)) model. Our data demonstrate that increasing rabeprazole dose up to 40 mg once daily results in an increasing pharmacodynamic effect, which is most apparent for the control of nocturnal gastric acid secretion.

The effect of CYP2C19 activity on pharmacokinetics of lansoprazole and its active metabolites in healthy subjects

Context: Lansoprazole is a gastric proton-pump inhibitor and has been demonstrated to be effective in the treatment of various peptic diseases. The effects of CYP2C19 activity on the pharmacokinetics of lansoprazole and its active metabolites in Chinese subjects have not previously been evaluated.Objective: The study aimed to evaluate the effects of CYP2C19 activity in healthy Chinese volunteers.Materials and methods: Twenty-two healthy volunteers were recruited for an open trial and received a single dose of 30 mg lansoprazole. Using a validated LC-MS/MS method, we measured the plasma concentrations of lansoprazole, 5-hydroxylansoprazole, and lansoprazole sulfone. The genotype of CYP2C19 was identified by polymerase chain reaction (PCR) analysis of single nucleotide polymorphisms (SNPs). Subjects were genotypically classified into the following three groups on the basis of PCR-SNP analysis for CYP2C19: homozygous EM (hmEM) group, heterozygous EM (htEM) group, and PM group. To test differences in pharmacokinetic parameters among the three groups, analysis of variance (ANOVA) after log-transformation of data was used.Results and conclusion: Our results indicated that there were significant differences (p < 0.001) between the hmEM and PM groups, between the htEM and PM groups, and between the hmEM and htEM groups in Cmax, AUC0–t, and AUC0–inf of lansoprazole and lansoprazole sulfone. There were also significant differences (p < 0.001) between the hmEM and PM groups, and between the htEM and PM groups in Cmax of 5-hydroxylansoprazole.

Effects of erythromycin on voriconazole pharmacokinetics and association with CYP2C19 polymorphism

PurposeTo assess the impacts of erythromycin on the pharmacokinetics of voriconazole and its association with CYP2C19 genotypes in healthy Chinese male subjects.MethodsA single-center, open, crossover clinical study with two treatment phases was carried out. Eighteen healthy male volunteers, including 6 CYP2C19 homozygous extensive metabolizers (EMs, *1/*1), 6 heterozygous EMs (HEMs, *1/*2 or *1/*3), and 6 CYP2C19 poor metabolizers (PMs, *2/*2 or *2/*3), were enrolled in this study. A single oral dose of 200 mg voriconazole was administrated to all subjects after 3-day pretreatment with either 500 mg erythromycin or placebo three times daily. Periods were separated by a washout period of 14 days. Serial venous blood samples were collected, and plasma concentrations of voriconazole were determined by HPLC.ResultsCmax, AUC0–24, and {hbox{AU}}{{hbox{C}}_{0 - infty }} of voriconazole were increased significantly, while oral clearance of voriconazole was decreased significantly by erythromycin administration (p < 0.001, respectively). Compared with individuals with CYP2C19 PM genotypes, individuals with CYP2C19 EM and HEM genotypes showed significantly decreased T½, AUC0–24, {hbox{AU}}{{hbox{C}}_{0 - infty }} , and increased oral clearance of voriconazole (p < 0.05, respectively). In addition, significant increases in AUC0–24 and {hbox{AU}}{{hbox{C}}_{0 - infty }} and decreases in oral clearance of voriconazole after erythromycin treatment were observed in CYP2C19 HEMs and PMs (p < 0.05, respectively), but not in CYP2C19 EMs.ConclusionBoth CYP2C19 genotypes and CYP3A4 inhibitor erythromycin can influence the plasma concentration of voriconazole, and erythromycin increases plasma concentration of voriconazole in a CYP2C19 genotype-dependent manner.

Influence of CYP2C19 genotype on the pharmacokinetics of R483, a CYP2C19 substrate, in healthy subjects and type 2 diabetes patients

R483 is a thiazolidinedione peroxisome proliferator-activated receptor gamma (PPARγ) agonist with anti-diabetic properties and also a cytochrome P450 2C19 (CYP2C19) substrate. The aim of the clinical studies reported here was to investigate the influence of the CYP2C19 genotype on the pharmacokinetics (PK) of R483 in healthy subjects and in type 2 diabetes mellitus (T2DM) patients. data came from two clinical studies, one including 58 Japanese and Caucasian healthy subjects and another including 93 Asian T2DM patients. All subjects received multiple doses of R483, 20 mg once daily for the healthy subjects and 12 mg once daily for the T2DM patients. Blood samples were taken up to 24 h after the last dose to determine plasma concentrations of R483 and its major metabolites. poor metabolizers (PMs; CYP2C19*2/*2 or *2/*3 or *3/*3) had a higher plasma exposure and a lower clearance of the parent drug than extensive metabolizers (EMs; CYP2C19*1/*1 or *1/*2 or *1/*3). The homozygous PM/EM ratio for the area under the plasma concentration-time curve (AUC(0-24)) [95% confidence interval] was 3.9 [2.7-5.7] for healthy subjects versus 2.0 [1.5-2.6] in T2DM patients. The heterozygous EMs were all T2DM patients, the PM/EM ratio for AUC(0-24) was 1.5 [1.2-1.8]. The dose-normalized exposure to R483 was 1.2- (for PMs) and 2.4-fold (for EMs) higher in T2DM patients than in healthy subjects. R483 was well tolerated in both studies. the plasma exposure to R483 was significantly higher in PMs than in EMs. R483 exhibits different PK in healthy subjects and T2DM patients, and the difference in exposure between EM and PM was less pronounced in T2DM patients than in healthy subjects. Factors such as diabetes condition and age may influence the metabolism of R483. This knowledge allowed for a realistic dose recommendation for poor metabolizer T2DM patients.

Correlation between R/S enantiomer ratio of lansoprazole and CYP2C19 activity after single oral and enteral administration

The purpose of this study was to investigate whether CYP2C19 activity can be estimated from plasma concentrations of lansoprazole enantiomers 4 h (C(4h)) after single administration by oral and enteral routes. Sixty-nine subjects, 22 homozygous extensive metabolizers (homEMs), 32 heterozygous EMs (hetEMs), and 15 poor metabolizers (PMs), participated in the study. After a single oral or enteral dose of racemic lansoprazole (30 mg), plasma concentrations of lansoprazole enantiomers were measured 4 h postdose. The R/S ratio of lansoprazole at 4 h differed significantly among the three groups (P < 0.0001) regardless of the administration route. The R/S ratio of lansoprazole in CYP2C19 PMs ranged from 3.0 to 13.7, whereas in homEMs and hetEMs the ratio ranged from 8.6 to 90 and 2.1 to 122, respectively. The relationship between (S)-lansoprazole concentration and R/S ratio of lansoprazole at C(4h) is given by the following formula: log(10) [R/S ratio] = 2.2 - 0.64 x log(10) [C(4h) of (S)-lansoprazole] (r = 0.867, P < 0.0001). Thus, phenotyping CYP2C19 using the R/S enantiomer ratio of lansoprazole seems unlikely. However, to obtain a pharmacological effect similar to that in CYP2C19 PMs, we can presume that lansoprazole has a sufficient effect in the patient with an R/S enantiomer ratio at 4 h < or = 13.70 and (S)-lansoprazole concentration at 4 h > or = 50 ng/ml.

Abstract 5010: Is Impact of Proton Pump Inhibitor on Platelet Reactivity to Clopidogrel A Class Effect?

Background: Concomitant administration of clopidogrel and proton pump inhibitor (PPI) is associated with the reduced effect on platelet response to clopidogrel, and increased risk of adverse outcome after stent placement in patients with acute coronary syndrome. However, it remains unknown whether all PPIs may reduce platelet inhibitory effects of clopidogrel. The aim of this study was to examine the impact of rabeprazole, which is one of PPIs and mostly not metabolized by CYP2C19, on platelet response to clopidogrel. Methods: Adenosine diphosphate (ADP) induced platelet aggregation (PA) using light transmission aggregometer (MCM HEMA TRACER 313) was measured as response to clopidogrel in 127 patients (male 64%, age68 years) with coronary artery disease (CAD), and CYP2C19 polymorphism, which is involved with metabolism of clopidogrel and PPI, is also examined using PCR. Results: CYP2C19 genotypes were divided into 3 groups such as homozygous extensive metabolizer (homoEM, n=46, CYP2C19*1/*1), heterozygous EM (heteroEM, n=52, *1/*2, *1/*3), and poor metabolizer (PM, n=29, *2/*2, *2/*3, *3/*3). In contrast to distribution of CYP2C19 polymorphism in Caucasian, the rate of CYP2C19 loss of function was higher in Japanese. ADP induced PA decreased significantly in homoEM, subsequently heteroEM, and was not well inhibited in PM (PA; 3250+/−1800, 4250+/−1300, and 5010+/−1370, respectively). However, ADP induced PA was not significantly different between patients treated with (n=29; PA=4637 +/−1800) and without rabeprazole (n=98; PA=3980 +/−1159). Moreover, there were no differences in ADP induced PA between groups with and without rabeprazole, in each subgroup categorized according to the genotype of CYP2C19. As to clinical events, the intake of PPI was not associated with increased risk of mortality and stent thrombosis in patients treated with stent delivery. Conclusion: In contrast to the reported negative PPI-clopidogrel drug interaction, the intake of rabeprazole is not associated with impaired response to clopidogrel and increased risk of mortality and stent thrombosis in patients with CAD.

Effects of CYP2D6 genotypes on age‐related change of flecainide metabolism: involvement of CYP1A2‐mediated metabolism

The aim of this study was to clarify the effects of CYP2D6 genotype on age-related change in flecainide metabolism in patients with supraventricular tachyarrhythmias. An in vitro study using microsomes was performed to identify other CYPs responsible for age-related change in flecainide metabolism. The study population comprised 111 genotyped patients: CYP2D6-homozygous extensive metabolizers (hom-EMs, n= 34), heterozygous EMs (het-EMs, n= 56), and intermediate and poor metabolizers (IMs/PMs, n= 21). Serum concentrations of flecainide and its metabolites [m-O-dealkylated flecainide (MODF) and m-O-dealkylated lactam of flecainide] were determined by use of a high-performance liquid chromatography. Metabolic ratio (MR) was expressed as serum concentrations of flecainide to its metabolites. In vitro formation of MODF was examined in human liver microsomes and cDNA-expressed CYP isoforms. MR was higher in elderly patients (> or =70 years) than in middle-aged patients (<70 years). The increase of MR in elderly patients differed among CYP2D6 genotypes: 1.6-fold in het-EMs [4.3, 95% confidence interval (CI) 2.8, 5.7 vs. 2.7, 95% CI 2.3, 3.1, P < 0.05], 1.5-fold in IMs/PMs (6.0, 95% CI 4.5, 7.6 vs. 4.1, 95% CI 2.9, 5.4, P < 0.05), and no change in hom-EMs. The in vitro study using microsomes revealed that both CYP2D6 and CYP1A2 were involved in the formation of MODF. MODF formation in CYP2D6 PM microsomes increased as CYP1A2 activity increased. The results suggest that patients with poor CYP2D6-mediated metabolism (het-EMs and IMs/PMs) showed age-related reduction in flecainide metabolism because metabolism was taken over by CYP1A2, whose activity decreases with age.

Pharmacokinetic– pharmacodynamic analysis of the role of CYP2C19 genotypes in short‐term rabeprazole‐based triple therapy against Helicobacter pylori

The aim was to explore the role of CYP2C19 polymorphism in short-term rabeprazole-based triple therapy against Helicobacter pylori infection. Patients with H. pylori infection were tested for CYP2C19 genotype as poor metabolizers (PMs) or extensive metabolizers (EMs, homozygous EM or heterozygous EM) and given rabeprazole for 7 days. Antibiotics (clarithromycin and amoxicillin) were given on days 1-4, days 4-7, or days 1-7. A direct link model with an effect compartment was used in the population pharmacokinetic-pharmacodynamic analysis. The status of H. pylori infection was evaluated. Rabeprazole clearance was lower in CYP2C19 PMs than in EMs (with average values of 10.7 vs. 16.8 l h(-1) in PMs and EMs, respectively), resulting in higher plasma levels in the former group. The values of EC(50) and k(eo) of gastrin response increased with multiple doses of rabeprazole. The k(eo) values were lower in CYP2C19 PMs than in EMs on day 1 (0.012 vs. 0.017 x 10(-4) l min(-1)), and higher than in EMs on day 4 (0.804 vs. 0.169 x 10(-4) l min(-1)) of rabeprazole treatment. The predicted gastrin-time profile showed a higher response in CYP2C19 PMs than in EMs on days 4 and 7. Helicobacter pylori was eradicated in all CYP2C19 PMs except in one patient infected by a resistant strain. In contrast, in CYP2C19 EMs the eradication rates ranged from 58 to 85%. CYP2C19 genotypes play a role in H. pylori eradication therapy. Rabeprazole-based short-term triple therapy may be applicable in CYP2C19 PMs for H. pylori eradication.

Optimal dose regimens of esomeprazole for gastric acid suppression with minimal influence of the CYP2C19 polymorphism

In this pilot study, we attempted to determine the optimal dosage regimens of esomeprazole for treatment of GERD with minimal influence of the CYP2C19 polymorphism through a study of the pharmacokinetics and pharmacodynamics of esomeprazole given at 3 different dosage regimens with the same total daily dose. Each of the 3 genotypes of CYP2C19, homozygous extensive metabolizers (homEMs), heterozygous EMS (hetEMs), and poor metabolizers (PMs) were recruited in this clinical trial. Subjects were given a placebo followed by the administration of esomeprazole, at a dose of 40 mg once daily (40QD), 20 mg twice daily (20TD), or 10 mg 4 times daily (10Q4D) for 7 days. Twenty-four-hour and nocturnal intragastric pH and plasma esomeprazole concentrations were all determined on day 7. The pharmacokinetic parameters and dynamic characteristics differed among the 3 CYP2C19 genotype groups. With esomeprazole 40QD, gastric acid suppression was insufficient to achieve a therapeutic effect, while 20TD and 10Q4D were found to be effective in controlling both daytime and nocturnal gastric acidity for all 3 genotype groups. It was confirmed that intragastric pH values and plasma esomeprazole concentrations potentially depended on the CYP2C19 genotype status for treatment with esomeprazole. Dosage regimens of divided doses of 20TD or 10Q4D esomeprazole yielded improved antisecretory effects with a minimal influence of CYP2C19 polymorphisms.

The Effect of CYP2C19 Polymorphism on the Pharmacokinetics and Pharmacodynamics of Clopidogrel: A Possible Mechanism for Clopidogrel Resistance

We evaluated the effect of the CYP2C19 genotype on the pharmacokinetics and pharmacodynamcis of clopidogrel. Twenty-four subjects were divided into three groups on the basis of their CYP2C19 genotype: homozygous extensive metabolizers (homoEMs, n = 8), heterozygous EMs (heteroEMs, n = 8), and poor metabolizers (PMs, n = 8). After a single 300-mg loading dose of clopidogrel on day 1, followed by a 75-mg daily maintenance dose from days 2 to 7, we measured the plasma levels of clopidogrel and assessed the antiplatelet effect as pharmacodynamics. The mean clopidogrel area under the curve (AUC) for PMs was 1.8- and 2.9-fold higher than that for heteroEMs and homoEMs, respectively (P = 0.013). The mean peak plasma concentration in PMs was 1.8- and 4.7-fold higher than that of heteroEMs and homoEMs, respectively (P = 0.008). PMs exhibited a significantly lower antiplatelet effect than heteroEMs or homoEMs (P < 0.001). From these findings it is clear that the CYP2C19 genotype affects the plasma levels of clopidogrel and modulates the antiplatelet effect of clopidogrel.

Cytochrome P450 2C19 polymorphism influences the preventive effect of lansoprazole on the recurrence of erosive reflux esophagitis

The efficacy of lansoprazole (LPZ) at inhibiting gastric acid secretion is influenced by cytochrome P450 2C19 (CYP2C19) polymorphism. The purpose of the present study was to investigate whether CYP2C19 polymorphism had an influence on the remission of erosive reflux esophagitis (RE) during maintenance therapy with LPZ. Eighty-two Japanese patients with initial healing of erosive RE by 8 weeks of LPZ therapy were enrolled. As maintenance therapy, the patients were treated with LPZ (15 mg/day) for 6 months. The CYP2C19 genotype, Helicobacter pylori infection status, and serum pepsinogen (PG) I/II ratio were assessed before treatment. The patients were investigated for relapse by endoscopy at 6 months or when symptoms recurred. The proportion of patients in remission after 6 months was 61.5%, 78.0%, and 100% among homozygous extensive metabolizers (homo-EM), heterozygous EM (hetero-EM), and poor metabolizers (PM), respectively. The percentage of PM patients who remained in remission was significantly higher than that of homo-EM or hetero-EM. The efficacy of LPZ (15 mg/day) as maintenance therapy for erosive RE is influenced by CYP2C19 polymorphism.

Absolute bioavailability and metabolism of omeprazole in relation to CYP2C19 genotypes following single intravenous and oral administrations

The aim of this study was to evaluate the absolute bioavailability and the metabolism of omeprazole following single intravenous and oral administrations to healthy subjects in relation to CYP2C19 genotypes. Twenty subjects, of whom 6 were homozygous extensive metabolizers (hmEMs), 8 were heterozygous EMs (htEMs) and 6 were poor metabolizers (PMs) for CYP2C19, were enrolled in this study. Each subject received either a single omeprazole 20 mg intravenous dose (IV) or 40 mg oral dose (PO) in a randomized fashion during 2 different phases. Mean omeprazole AUC (0,infinity) was 1164, 3093 and 10511 ng h/mL after PO, and 1435, 2495 and 6222 ng h/mL after IV in hmEMs, htEMs and PMs, respectively. Therefore, the absolute bioavailability of omeprazole in PMs was significantly higher than that in hmEMs (p < 0.001) and htEMs (p < 0.001). Hydroxylation metabolic indexes after IV and PO were significantly lower in PMs than in hmEMs (p < 0.001) and htEMs (p < 0.001), and was correlated with the absolute bioavailability (p < 0.0001 for both IV and PO). Sulfoxidation metabolic index after IV was significantly different between the CYP2C19 genotypes, whereas no difference was found after a single oral dose. This study indicates that the absolute bioavailability of omeprazole differs among the three different CYP2C19 genotypes after a single dose of omeprazole orally or intravenously. Hydroxylation metabolic index of omeprazole may be mainly attributable to the genotype of CYP2C19. As for the sulfoxidation metabolic index after a single oral dose, intestinal CYP3A may be contributed to omeprazole metabolism.