Heterozygous Extensive Metabolizers Research Articles

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metabolizers (CYP2C19*1/*2 or CYP2C19*1/*3), and 1 subject genotyped as a poor metabolizer (CYP2C19*2/*3) and was withdrawn from the research because of urticaria.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.

Western blotting analysis for quantitative detection of CYP2C19 expression in liver tissues in the setting of living donor liver transplantation.

The cytochrome P450 (CYP) drug-metabolizing enzymes play an important role in cellular metabolism. Therapeutic failure or drug toxicity in the period after liver transplantation (LT) is influenced by the drug metabolizing capacity of the graft. The expression levels of CYP2C19 enzyme are often used as an indicator of the functioning of the CYP system. The aim of the present study was to assess the CYP2C19 protein expression in the setting of living donor liver transplantation (LDLT) by using western blotting analysis. We performed CYP2C19 genotyping of liver biopsy samples obtained from 24 donors and 8 recipients each in the pre- and post-LT periods, after which we analyzed the CYP enzyme activity by using western blotting analysis. The CYP2C19/β-actin ratio, which was an indicator of CYP expression, was 61.75% (23-100%) in donors, 59.13% (15-100%) in pre-LT recipients and 46.71% (12-67%) in post-LT recipients (p>0.05). The CYP2C19 expression levels associated with different genotypes were as follows: homozygous extensive metabolizers (HomEMs; n=24), 56.63±24.74%; heterozygous extensive metabolizers (HetEMs; n=15), 63.0±25.14% and poor metabolizers (PMs; n=1), 82.0% (p>0.05). Western blotting analysis showed low CYP2C19 protein expression not only in samples from the pre- and post-LT recipients but also from the donors.

Effects of cytochrome P450 (CYP)2C19 polymorphisms on pharmacokinetics of phenobarbital in neonates and infants with seizures

BackgroundPhenobarbital (PB), commonly used as the preferred treatment for neonatal seizure, is a drug that requires careful dose adjustments based on therapeutic drug monitoring. It has been reported that PB...

Effect of CYP2C19 Polymorphism on the Pharmacokinetics of Voriconazole After Single and Multiple Doses in Healthy Volunteers

The current study assessed the influence of the CYP2C19 genotype on the pharmacokinetics and tolerability of voriconazole after single and multiple oral doses in healthy volunteers. Six subjects for the CYP2C19 homozygous extensive metabolizer (EMs), 6 for heterozygous extensive metabolizer (HEMs), and 6 for poor metabolizer (PMs) were enrolled, and their CYP2C9, CYP3A5, and MDR1 genotypes were analyzed. After a single intravenous infusion or single and multiple oral doses of 200 mg of voriconazole, plasma concentrations of voriconazole were measured. Bioavailability was not significantly different among the CYP2C19 genotypes. Voriconazole exposure in PMs was approximately 3 times higher compared with EMs after a single intravenous or oral dose. At steady state, the plasma concentration just before the next dosing and area under the concentration-time curve from dosing to the time point of the next dosing for PMs were about 5 times and 3 times higher than EMs, respectively. These results suggest that the CYP2C19 genotype is the major determinant of the wide PK variability of voriconazole.

Clinical Usefulness of Limited Sampling Strategies for Estimating AUC of Proton Pump Inhibitors

Cytochrome P450 (CYP) 2C19 (CYP2C19) genotype is regarded as a useful tool to predict area under the blood concentration-time curve (AUC) of proton pump inhibitors (PPIs). In our results, however, CYP2C19 genotypes had no influence on AUC of all PPIs during fluvoxamine treatment. These findings suggest that CYP2C19 genotyping is not always a good indicator for estimating AUC of PPIs. Limited sampling strategies (LSS) were developed to estimate AUC simply and accurately. It is important to minimize the number of blood samples because of patient's acceptance. This article reviewed the usefulness of LSS for estimating AUC of three PPIs (omeprazole: OPZ, lansoprazole: LPZ and rabeprazole: RPZ). The best prediction formulas in each PPI were AUC(OPZ)=9.24 x C(6h)+2638.03, AUC(LPZ)=12.32 x C(6h)+3276.09 and AUC(RPZ)=1.39 x C(3h)+7.17 x C(6h)+344.14, respectively. In order to optimize the sampling strategy of LPZ, we tried to establish LSS for LPZ using a time point within 3 hours through the property of pharmacokinetics of its enantiomers. The best prediction formula using the fewest sampling points (one point) was AUC(racemic LPZ)=6.5 x C(3h) of (R)-LPZ+13.7 x C(3h) of (S)-LPZ-9917.3 x G1-14387.2×G2+7103.6 (G1: homozygous extensive metabolizer is 1 and the other genotypes are 0; G2: heterozygous extensive metabolizer is 1 and the other genotypes are 0). Those strategies, plasma concentration monitoring at one or two time-points, might be more suitable for AUC estimation than reference to CYP2C19 genotypes, particularly in the case of coadministration of CYP mediators.

A Case of Visual and Auditory Hallucinations during Intravenous Voriconazole Therapy

Voriconazole is a triazole with broad spectrum antifungal activity, and it is currently considered to be the first-line agent for the treatment of invasive aspergillosis. We report here on a case of visual and auditory hallucinations during intravenous treatment with voriconazole in association with a high trough level. A 28-year-old man with acute myelogenous leukemia was admitted for re-induction remission chemotherapy. During the persistent neutropenic fever, intravenous voriconazole was administered for the suspected invasive fungal pneumonia. He began to have visual hallucinations on the 1st day and auditory hallucinations on the 3rd day of voriconazole therapy. The plasma peak and trough concentration levels of voriconazole were 9.9 and 7.4 μg/ml, respectively, on the 3rd day. The hallucinations resolved after changing to amphotericin B deoxycholate, and the plasma concentration of voriconazole dropped to less than 0.5 μg/ml. The genotype of the CYP2C19 alleles was classified as a heterozygous extensive metabolizer. We suggest that therapeutic drug monitoring of voriconazole is indicated for a case that is suspicious for a voriconazole-related adverse event.

Efficacy and tolerability of first-line triple therapy with levofloxacin and amoxicillin plus esomeprazole or rabeprazole for the eradication of Helicobacter pylori infection and the effect of CYP2C19 genotype: A 1-week, randomized, open-label study in chinese adults

Background: First-line triple therapy with levofloxa- cin and amoxicillin plus a proton pump inhibitor has been reported to be effective and well tolerated in the eradication of Helicobacter pylori infection. Studies have reported that cytochrome P450 (CYP) 2C19 genotypes may affect the clinical efficacy of clarithromycinbased triple therapies, although there is only one report of such an effect with levofloxacin-based triple therapies. Objectives: This study evaluated the clinical efficacy and tolerability of a 1-week course of triple therapy with levofloxacin and amoxicillin plus esomeprazole or rabeprazole as first-line treatment for H pylori infection in Chinese adults. It also investigated whether CYP2C19 genotype status affected rates of H pylori eradication with these regimens. Methods: Consecutive patients undergoing upper endoscopy at the First Affiliated Hospital of Nanjing Medical University between May 2008 and January 2009 were evaluated for inclusion. Eligible patients were those who tested positive for H pylori infection on biopsy-based testing (ie, histology and an in-house rapid urease test) or a validated 13C-urea breath test. Patients were randomized in an open-label fashion to receive levofloxacin 500 mg/d and amoxicillin 1000 mg BID plus either esomeprazole 20 mg BID (group A), esomeprazole 40 mg BID (group B), or rabeprazole 10 mg BID (group C) for 1 week. Patients were asked to record adverse events in a diary. Trained study assistants contacted patients by telephone within the first week after completion of therapy to collect data on drug compliance and adverse events. H pylori status was determined 4 weeks after the end of therapy using a 13C-urea breath test. Rates of H pylori eradication were calculated in the intent-to-treat (ITT) and per-protocol (PP) populations. CYP2C19 genotype was determined by the polymerase chain reaction-restriction fragment-length polymorphism method. Results: Of 199 consecutive patients screened for eligibility, 184 H pylori-positive patients were enrolled in the study (61 in group A, 62 in group B, and 61 in group C). The overall sample was balanced in terms of age, sex, endoscopic diagnosis, and history of smoking. Rates of H pylori eradication in the ITT and PP populations were as follows: group A—85.2% (52/61) and 86.7% (52/60), respectively; group B—87.1% (54/62) and 90.0% (54/60); and group C—75.4% (46/61) and 75.4% (46/61). There were no significant differences in eradication rates among groups, nor were there any differences in rates of compliance (98.4%, 96.8%, and 100% in groups A, B, and C, respectively) or adverseevent profiles. Fifteen patients (7.6%) reported adverse events during the study (5 [8.2%] in group A, 6 [9.7%] in group B, and 4 [6.6%] in group C). The adverse events included diarrhea (6 patients), dizziness (5), abdominal pain (2), nausea (1), and skin rash (1). Three patients discontinued treatment because of adverse events ( 1 due to skin rash in group A and 2 due to dizziness in group B). In the 147 patients included in the PP analysis of the effect of CYP2C19 genotype, eradication rates were 88.9% (32/36) in poor metabolizers, 82.0% (50/61) in heterozygous extensive metabolizers, and 82.0% (41/50) in homozygous extensive metabolizers. Eradication rates did not differ significantly among genotype groups. Conclusions: One week of first-line triple therapy with levofloxacin and amoxicillin plus esomeprazole 20 or 40 mg BID or rabeprazole 10 mg BID was associated with H pylori eradication rates of 85.2%, 87.1%, and 75.4%, respectively, with no significant differences between treatment groups. There were no significant differences in eradication of H pylori by CYP2C19 genotype in this small population of Chinese adults.

Pantoprazole Induced Elevation of Transaminases: A Case Report and Literature Review

Purpose: Case Report: An 88-year-old female was treated for infectious colitis. On admission, the transaminases, alkaline phosphatase and total bilirubin were normal. On Day 2 of hospitalization she was started empirically on oral pantoprazole for a history of peptic ulcer disease. By Day 4 the transaminases were noted to be increasing. Viral and autoimmune hepatitis evaluations were negative. There was no hypotension. Ultrasound of the liver was normal. The only potentially hepatotoxic agents were pantoprazole, simvastatin and metoprolol. The pantoprazole was stopped on Day 6 and the other medications were continued. The transaminases began to normalize. Discussion: PPI are a substituted benzimidazole that inhibits gastric acid secretion by interference with proton pumps on the secretory membrane of parietal cells. Compounds containing benzimidazole are metabolized by CYP2C19. Polymorphisms of the gene result in 3 distinct phenotypes. These are homozygous extensive metabolizer (homEM), heterozygous extensive metabolizer (hetEM) and poor metabolizer (PM). The plasma level of omeprazole is sustained for much longer in PM and can be as high as the peak concentration in persons who are homEM. In addition, the area under the curve for PM may be 13 times as high at homEM. Patients with GERD positive for mucosal breaks were treated for 8 weeks with 30 mg of lansoprazole. Cure rates based on endoscopy were lowest in homoEM followed by heteEM. The PM group was highest due to high plasma lansoprazole levels and less frequent nocturnal acid breakthrough (NAB). Higher doses of PPI are required for treatment and maintenance. Reported long term effect of PPI on human body includes increased gastrin level, megaloblastic anemia and atrophic gastritis. In children, long term use of PPI is safe and well tolerated. Hepatitis has been seen in several PPI. In a report of fulminant hepatic failure post mortem examination of the liver demonstrated massive central zone necrosis (5,9). Some elecations of transaminases are benign and have been reported in <1% of all patients taking omeprazole. Most elevations returned to normal in a few days and all returned to normal after 6 weeks. In the non-ICU setting, there is widespread use of PPI for stress ulcer prophylaxis or GI prophylaxis, on the basis of potential adverse effects and substantial health care cost the inappropriate use of PPI should be discouraged.

CYP2D6 Polymorphisms as Predictors of Outcome in Breast Cancer Patients Treated with Tamoxifen: Expanded Polymorphism Coverage Improves Risk Stratification

This study aimed to validate matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS)/Taqman copy number assay (CNA) CYP2D6 genotyping by AmpliChip CYP450 Test for the prediction of tamoxifen metabolizer phenotypes in breast cancer, and to investigate the influence of CYP2D6 variant coverage on genotype-phenotype relationships and tamoxifen outcome. Hormone receptor-positive postmenopausal breast cancer patients (n = 492) treated with adjuvant tamoxifen, previously analyzed by MALDI-TOF MS/CNA, were reanalyzed by AmpliChip CYP450 Test and validated by independent methods. Cox proportional hazard ratios (HR) were calculated for recurrence of poor (PM) relative to extensive metabolizer (EM) phenotypes with increasing numbers of CYP2D6 variants. Kaplan-Meier distributions were calculated for different phenotype classifications. Concordance was 99.2% to 99.5% for CNA and 99.8% to 100% per CYP2D6 allele (*3, *4, *5, *9, *10, and *41). The prevalence of predicted phenotypes was 1.2% for ultrarapid metabolizer (UM), 37.2% for EM without variant, 43.5% for heterozygous EM, 9.7% for intermediate metabolizer (IM), and 8.3% for PM. Approximately, one third of patients were misclassified based on a *4 analysis only, but inclusion of all reduced-function alleles increased the PM-associated HR from 1.33 (P = 0.58) to 2.87 (P = 0.006). Kaplan-Meier analyses showed highest and lowest clinical benefit for UM and PM with respect to both the AmpliChip-based and a redefined phenotype assignment. The latter revealed significant allele-dose-dependent associations (P = 0.011) and largest effect size (HR(PM_EM) = 2.77; 95% confidence interval, 1.31-5.89). MALDI-TOF MS/CNA is suitable for accurate CYP2D6 genotyping. For tamoxifen pharmacogenetics, broad CYP2D6 allele coverage is recommended to reduce phenotype misclassification. Classification based on refined EM and reduced-function metabolizers is advisable. AACR.

Relationship between the Acid-Inhibitory Effects of Two Proton Pump Inhibitors and CYP2C19 Genotype in Japanese Subjects: A Randomized Two-Way Crossover Study

This two-way crossover study investigated possible differences between the proton pump inhibitors, omeprazole and rabeprazole, in their effect on gastric acid secretion in Japanese subjects with differing cytochrome P450, family 2, subfamily C, polypeptide 19 (CYP2C19) genotypes. A total of 23 Helicobacter pylori-negative healthy volunteers received omeprazole 20 mg/day and rabeprazole 10 mg/day. Each drug treatment was given for a continuous 7-day period allocated in random order, with an interval of at least 1 week between drug treatment periods to allow for wash-out. Intragastric pH was measured on days 1 and 7. Overall median intragastric pH levels at 7 and 8 h after the first administration were significantly higher with omeprazole. There was no significant difference in intragastric pH in homozygous extensive metabolizers, whereas intragastric pH was significantly higher with omeprazole in combined data from heterozygous extensive metabolizers and poor metabolizers at 6, 7 and 8 h after the first drug administration. There were no significant differences in intragastric pH between omeprazole and rabeprazole irrespective of genotype on day 7 of administration. In conclusion, on day 1 the time to onset of the antisecretory action of 20 mg/day omeprazole was more rapid than that of 10 mg/day rabeprazole in Japanese individuals who have a higher incidence of the CYP2C19 poor metabolizer genotype, however by day 7 no difference in antisecretory effect was found, regardless of genotype.

The Influence of CYP2C19 Polymorphism on Eradication of Helicobacter pylori: A Prospective Randomized Study of Lansoprazole and Rabeprazole

The CYP2C19 polymorphism plays an important role in the metabolism of various proton-pump inhibitors. Several trials have produced conflicting data on eradication rates of Helicobacter pylori (H. pylori) among CYP2C19 genotypes. We investigated whether the CYP2C19 genotype affects the eradication rate of H. pylori by direct comparing the effects of lansoprazole- and rabeprazole-based triple therapies. A total of 492 patients infected with H. pylori was randomly treated with either 30 mg of lansoprazole or 20 mg of rabeprazole plus 500 mg of clarithromycin and 1,000 mg of amoxicillin twice daily for 1 week. CYP2C19 genotype status was determined by a PCR-restriction-fragment-length polymorphism method. After 7 to 8 weeks, H. pylori status was evaluated by a C(13)-urea breath test. Four hundred and sixty-three patients were analyzed, and the eradication rate was 75.2% in a per-protocol analysis. Eradication rates for the lansoprazole regimen (n=234) were 73.8%, 80.7%, and 85.4% in the homozygous extensive (HomEM), heterozygous extensive (HetEM), and poor metabolizers (PM) groups, respectively (p=0.303). In the case of the rabeprazole regimen (n=229), the eradication rates were 68.6%, 73.0%, and 71.9% in the HomEM, HetEM, and PM groups, respectively (p=0.795). The efficacies of triple therapies that include lansoprazole or rabeprazole are not affected by CYP2C19 genetic polymorphisms.

Influence of CYP2C19 on the relationship between pharmacokinetics and intragastric pH of omeprazole administered by successive intravenous infusions in Chinese healthy volunteers

To explore the effect of cytochrome P450 2C19 (CYP2C19) polymorphisms on the relationship between the pharmacokinetics and pharmacodynamics of omeprazole administered by intravenous successive infusions in Chinese healthy volunteers. A total of 21 subjects [7 homozygous extensive metabolizers (homEMs), 9 heterozygous extensive metabolizers (hetEMs), 5 poor metabolizers (PMs)] received a 5-day course of omeprazole (40 mg) administered as a single dose daily during a 30-min period. Plasma concentrations were monitored by sampling at very short intervals for the first 8.5 h post-omeprazole administration and at 24 h post-administration, and intragastric pH was recorded on days 1 and 5. After a single dose, both the area under the plasma concentration-time curve (AUC) and peak concentration (C(max)) were higher in PMs than in EMs. Both the mean half-life (t((1/2))) and total clearance in PMs were significantly higher and lower than those in homEMs and EMs, respectively. Mean AUC and C(max) ratios in homEMs, hetEMs, and PMs were 1.0:1.1:1.4 and 1.0:1.0:1.1, respectively. Relative to the values determined after a single dose in EMs, after repeated doses, the intragastric pH, AUC, C(max), and t((1/2)) had increased significantly, while the total clearance had decreased significantly. Mean AUC and C(max) ratios in homEMs, hetEMs, and PMs were 1.4:1.4:1.5 and 1.2:1.2:1.3, respectively, compared to those of a single dose. The mean intragastric pH was significantly higher in PMs than in EMs after the fifth dose. There is a relationship between the pharmacokinetics and pharmacodynamics of omeprazole, with the latter depending in part on the duration of administration as evidenced by a higher AUC or C(max) and intragastric pH resulting from repeated dosing.

Association Between &lt;emph type="ital"&gt;CYP2D6&lt;/emph&gt; Polymorphisms and Breast Cancer Outcomes

To the Editor: In their cohort study, Dr Schroth and colleagues reported an association between CYP2D6 polymorphisms and breast cancer outcomes among women treated with tamoxifen. Although the authors described their study as adequately powered, it appears that their power calculations did not account for the substantial overlap between the outcomes reported in this study and the outcomes described in 2 earlier reports. This overlapping sample violates the independent trials assumption that underlies all frequentist statistics, including power calculations. Moreover, the authors did not report the association between CYP2D6 polymorphisms and breast cancer outcomes observed only in the person-time that had not been included in the earlier reports. This association would be helpful in meta-analyses that synthesize the available evidence. For example, the hazard ratio (HR) for the association between decreased metabolism (compared with extensive metabolism) and recurrence can be estimated as 1.50 (95% confidence interval [CI], 1.15-1.96). I calculated this HR as an inverse variance-weighted average of the adjusted associations reported in Table 3: heterozygous extensive metabolizers and intermediate metabolizers vs extensive metabolizers (HR, 1.40; 95% CI, 1.041.90), averaged with poor metabolizers vs extensive metabolizers (HR, 1.90; 95% CI, 1.10-3.28). This averaged HR should itself be an inverse-variance weighted average of (1) the unreported adjusted association in the new persontime, (2) the comparable adjusted HR reported by Goetz et al (HR, 1.91; 95% CI, 1.05-3.45), and (3) the comparable adjusted HR reported earlier by Schroth et al (HR, 2.24; 95% CI, 1.16-4.33). I estimate that the missing adjusted association in the new person-time is HR, 1.26 (95% CI, 0.911.76). It would be far better, however, if the authors would provide the estimate of this association and its CI.

T1085 Effect of CYP2C19 Genotype On Control of Gastric Acidity with Rabeprazole and Esomeprazole After Single and Repeated Oral Administration

Introduction: Esomeprazole (eso) and rabeprazole (rabe) are metabolized in the liver. Genetic polymorphism of the cytochrome P-450 enzyme CYP2C19 determines fast (homozygous extensive metabolizers, wt/wt), intermediate (heterozygous extensive metabolizers, wt/∗2 or wt/∗3) and slow (poor metabolizers, ∗2/∗2, ∗3/∗3 or ∗2/∗3) or rapid (wt/∗17 or ∗17/∗17) metabolism of proton pump inhibitors (PPIs). In the Caucasian population 60% has the wt/ wt genotype, 30-40% is wt/∗2 and 2-5% ∗2/∗2. Aim: To investigate the impact of CYP2C19 genotype on control of gastric acidity (median pH and % of time pH

O-demethylation of codeine to morphine inhibited by low-dose levomepromazine

Codeine/paracetamol (C/P) and levomepromazine (L) are frequently co-administered for the treatment of acute back pain, but the efficacy/effectiveness of this combination drug therapy has not been evaluated. The demethylation of codeine to morphine is catalyzed by the polymorphic enzyme cytochrome P450 2D6 (CYP2D6), of which levomepromazine (methotrimeprazine) is a known inhibitor. The aim of this study was to investigate whether low-dose levomepromazine inhibits the formation of morphine from codeine in a patient population of homozygous extensive (EM) and heterozygous extensive (HEM) metabolizers of CYP2D6. Our patient cohort consisted of 29 patients hospitalized for acute back pain who were randomized to a 24-h treatment with either C/P (60 mg codeine + 1000 mg paracetamol) four times daily or to L+C/P (levomepromazine 5 + 5 + 5 + 10 mg + C/P) four times daily. After zero-urine sampling (baseline), the treatment was started and urine collected for 24 h. Blood samples were later genotyped for the CYP2D6*3, *4, and *6 polymorphisms by the PCR (LightCycler system) and for the *5 polymorphism using long PCR, to identify EM and HEM and to eliminate CYP2D6 poor metabolizers. Urine samples were analyzed using the CEDIA immunoassay and gas chromatography-mass spectrometry after enzymatic hydrolysis of glucuronide conjugates. O-demethylation ratios of codeine were calculated as hydrolyzed (total) concentrations of morphine/morphine + codeine. Twenty-two of the patients fulfilled the inclusion criteria, of whom ten were EM (five C/P and five L+C/P) and twelve were HEM (six C/P and six L+C/P) for functional CYP2D6 alleles. In the EM group, the median O-demethylation ratio was significantly higher (P = 0.016, Mann-Whitney test) after the C/P treatment (0.092, range 0.041-0.096) than after the L+C/P treatment (0.031, range 0.009-0.042). However, there was no significant difference between these two treatments in either the HEM group [n = 12; 0.024 (range 0.011-0.042) vs. 0.026 (range 0.009-0.041), respectively; P = 1.00] or in the combined EM/HEM group [11 C/P + 11 L+C/P; 0.041 (range 0.011-0.096) vs. 0.030 (range 0.009-0.042), respectively; P = 0.122]. Our study revealed significant inhibition in the O-demethylation of codeine to morphine in homozygous EM of CYP2D6 treated with low-dose levomepromazine and codeine/paracetamol, compared to treatment with codeine/paracetamol only. No significant difference could be detected in HEM or in the mixed and heterogenous group of EM/HEM. In patients prescribed this drug combination, the amount of morphine generated by the O-demethylation of codeine may be insufficient for effective pain relief. The therapeutic effect of codeine in the treatment of acute back pain should be assessed with and without levomepromazine.

Effects of CYP2C19 and MDR1 genotype on the eradication rate of Helicobacter pylori infection by triple therapy with pantoprazole, amoxycillin and clarithromycin

CYP2C19 polymorphism plays an important role in the metabolism of proton pump inhibitors. The multidrug resistance (MDR)1 genotype is associated with the successful eradication of Helicobacter pylori. The aim of the present study was to investigate the effects of CYP2C19 and MDR1 genotypes on the eradication rate of H. pylori using a pantoprazole-based triple therapy. A total of 210 patients infected with H. pylori were treated with 40 mg pantoprazole, 500 mg clarithromycin and 1000 mg amoxicillin twice daily for 7 days. The CYP2C19 genotype was determined with polymerase chain reaction (PCR)-restriction fragment length polymorphism analysis. The MDR1 C3435T polymorphism was identified by PCR-based allele-specific amplification (PCR-ASA). Of the 210 patients who completed the study, 174 (82.9%, 95.0% confidence interval [CI], 77.8-88.0%) achieved successful eradication after the first cycle of therapy. The eradication rates for H. pylori were 86.7%, 81.1% and 82.1% in the homozygous extensive, heterozygous extensive and poor metabolizer groups, respectively (P = 0.65). Moreover, the cure rates in the CC, CT, and TT groups were 82.7%, 84.4% and 76.9%, respectively (P = 0.66). Multiple logistic regression analysis revealed that endoscopic diagnosis was a significant independent risk factor for treatment failure. The eradication rates of H. pylori by pantoprazole, amoxicillin and clarithromycin were not significantly different among the CYP2C19 and MDR1 genotypes. Hence, the cure rate of H. pylori in the Korean population was no different for the CYP2C19 and MDR1 genotypes.

Hot flashes are associated with CYP2D6 genotype in breast cancer survivors taking tamoxifen.

Abstract Abstract #6045 Background: We have previously shown that participants in the Women's Healthy Eating and Living (WHEL) study comparison group who reported hot flashes after breast cancer treatment had more favorable disease-free survival than women who did not report hot flashes. However, this was not the case in the intervention group. The polymorphic CYP450 enzyme CYP2D6 catalyzes the conversion of tamoxifen (TAM) to one of its key active metabolites, endoxifen. Some studies have suggested that certain genetic variants of CYP2D6 are associated with a decreased likelihood of hot flashes, reduced endoxifen levels and an increased risk of disease recurrence in women receiving adjuvant TAM therapy. This analysis was performed to estimate the association between CYP2D6 genotype and hot flashes in early stage breast cancer survivors who took adjuvant TAM in the WHEL study.&amp;#x2028; Methods: The WHEL study was a randomized trial of a dietary intervention in breast cancer survivors, who enrolled in the study within 4 years of diagnosis from 1995-2000. Participants self-reported TAM use, hot flash severity and menopausal status at study entry. Clinical characteristics (tumor stage, estrogen receptor status, chemotherapy) were extracted from medical records. Blood samples were obtained by venipuncture, separated and stored at -80 deg. DNA was extracted from stored buffy coat and analyzed using the Roche AmpliChip CYP450 Test. Women were classified according to their predicted CYP2D6 phenotype as Extensive (EM), Heterozygous Extensive (Het EM), Intermediate (IM), Poor (PM), or Ultrarapid (UM) Metabolizers.&amp;#x2028; Results: Overall, 1434 WHEL participants had verified estrogen receptor-positive stage I or II breast cancers and reported taking TAM at baseline for at least 4 months. A total of 1411 women were successfully genotyped and their CYP2D6 phenotypes were classified as follows: 468 EM (33.2%); 665 Het EM(47.1%), 164 IM (11.6%), 86 PM (6.1%) and 28 UM (2.0%). In univariate analyses, there was a significant difference among CYP2D6 genotype in relation to hot flashes reported at baseline: 79.8% of EMs, 76.3% of Het EMs, 80.1% of IMs, 63.9% of PMs, and 75% of UMs reported hot flashes (χ2= 11.3, p=0.02). After controlling for age, menopausal status, and time since diagnosis, the PM group was half as likely to report hot flashes as the referent EM group (OR= 0.46; 95% CI= 0.28-0.78; p=0.003). Additional analyses of serum endoxifen levels and associations with disease outcome are underway.&amp;#x2028; Conclusion: In the WHEL study, women who were classified as Poor Metabolizers of TAM, based on their CYP2D6 genotype, were half as likely as Extensive Metabolizers to report experiencing hot flashes while receiving adjuvant TAM treatment for early stage breast cancer. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6045.

Steady-State Concentrations of Mirtazapine, N-Desmethylmirtazapine, 8-Hydroxymirtazapine and their Enantiomers in Relation to Cytochrome P450 2D6 Genotype, Age and Smoking Behaviour

Mirtazapine is a tetracyclic antidepressant drug available as a racemic mixture of S(+)- and R(-)-mirtazapine. These enantiomers have different pharmacological properties, and both contribute to the clinical and adverse effects of the drug. Cytochrome P450 (CYP) 2D6 has been implicated in the metabolism of S(+)-mirtazapine. However, the effect of CYP2D6 on serum concentrations of the enantiomers of mirtazapine and its metabolites has not been assessed in patients on long-term treatment. The main objective of the study was to evaluate the effect of the CYP2D6 genotype on enantiomeric steady-state trough serum concentrations of mirtazapine and its metabolites N-desmethylmirtazapine and 8-hydroxymirtazapine. The effects of sex, age and smoking behaviour were also assessed. The study included 95 patients who had depression according to the Diagnostic and Statistical Manual of Mental Disorders-4th Edition and were treated for 4 weeks with a daily dose of mirtazapine 30 mg. The serum concentrations of the enantiomers of mirtazapine and its metabolites were analysed by liquid chromatography-mass spectrometry, and the subjects were genotyped for CYP2D6 alleles *3, *4, *5 and *6 and gene duplication. Three subjects (3%) were classified as ultrarapid metabolizers (UMs), 56 (59%) as homozygous extensive metabolizers (EMs), 30 (32%) as heterozygous EMs and 6 (6%) as poor metabolizers (PMs) of CYP2D6. The median trough serum concentrations of S(+)-mirtazapine were higher in PMs (59 nmol/L, p = 0.016) and in heterozygous EMs (39 nmol/L, p = 0.013) than in homozygous EMs (28 nmol/L). PMs and heterozygous EMs also had higher mirtazapine S(+)/R(-) ratios (0.4) than homozygous EMs (0.3, p = 0.015 and 0.004, respectively). The S(+)-N-desmethylmirtazapine concentration was higher in PMs (16 nmol/L) than in homozygous EMs (7 nmol/L, p = 0.043). There was an association between the CYP2D6 genotype and the ratio between S(+)-8-hydroxymirtazapine and S(+)-mirtazapine, with a significantly higher ratio in homozygous EMs than in heterozygous EMs (0.11 vs 0.05, p = 0.007). The influence of the CYP2D6 genotype on S(+)-mirtazapine, the mirtazapine S(+)/R(-) ratio and S(+)-N-desmethylmirtazapine remained significant after correction for the influence of sex, age and smoking. Smokers had significantly lower concentrations of S(+)-mirtazapine (23 vs 39 nmol/L, p = 0.026) and R(-)-N-desmethylmirtazapine (39 vs 51 nmol/L, p = 0.036) and a significantly lower mirtazapine S(+)/R(-) ratio (0.28 vs. 0.37, p = 0.014) than nonsmokers, and the effect of smoking remained significant after multivariate analysis. This study is the first to show the impact of the CYP2D6 genotype on steady-state serum concentrations of the enantiomers of mirtazapine and its metabolites. Our results also support the role of CYP1A2 in the metabolism of mirtazapine, with lower serum concentrations in smokers than in nonsmokers.

Effect of CYP2C19 Genetic Polymorphisms on the Efficacy of Proton Pump Inhibitor‐Based Triple Therapy for Helicobacter pylori Eradication: A Meta‐Analysis

CYP2C19 polymorphisms have been inconsistently reported to associate with the efficacy of proton pump inhibitor (PPI)-based triple therapies for eradicating Helicobacter pylori infection. The aim of this meta-analysis was to determine whether CYP2C19 polymorphism affect H. pylori eradication rates obtained with first-line PPI-based triple therapies. A systematic literature search was conducted up to July 2007 using Medline, PubMed, EMBase, Cochrane Central Register of Controlled Trials (CENTRAL), ISI Web of Science, CNKI (Chinese), and Wanfang (Chinese) digital database. MeSH terms and keywords included proton pump inhibitor, omeprazole, lansoprazole, rabeprazole, pantoprazole, or esomeprazole, cytochrome P4502C19 or CYP2C19, and Helicobacter pylori or H. pylori. Twenty articles met the inclusion criteria, and were included in the meta-analysis by using Review Manager 4.2.8. Eradication rates were significantly different between poor metabolizers (PM) and heterozygous extensive metabolizers (HetEM) (odds ratio (OR) = 1.73, p = .002) and between PM and homozygous extensive metabolizers (HomEM) (OR = 2.79, p < .0001). Moreover, eradication rates were also significant difference between HetEM and HomEM (OR = 2.00, p < .0001). Triple omeprazole and lansoprazole therapies achieved higher H. pylori eradication rates in PM than in HomEM (OR = 4.28, p = .0005 for omeprazole and OR = 3.06, p = .001 for lansoprazole), and higher in HetEM than those in HomEM (OR = 3.22, p < .0001 for omeprazole and OR = 1.95, p = .040 for lansoprazole). Rabeprazole therapies had no significant effect on H. pylori eradication rates (between PM and HomEM, OR = 1.35, p = .610 and between HetEM and HomEM, OR = 1.57, p = .190). No significant difference in H. pylori eradication rates between PM and HetEM was observed in the three individual PPI therapies. The efficacy of omeprazole- and lansoprazole-based first-line triple therapies at the standard doses is dependent on CYP2C19 genotype status, which appears not to affect the efficacy of the regimens including rabeprazole.

Population Estimation Regarding the Effects of Cytochrome P450 2C19 and 3A5 Polymorphisms on Zonisamide Clearance

We aimed to evaluate the effects of cytochrome P450 (CYP) 2C19 and CYP3A5 polymorphisms on zonisamide (ZNS) clearance. The pharmacokinetics of the 282 ZNS concentrations at a steady state obtained from 99 Japanese epileptic patients was performed with a nonlinear mixed-effect modeling program, using a one-compartment open pharmacokinetic model with first-order elimination. The covariates screened included the total body weight, gender, ZNS daily dose, CYP2C19 and CYP3A5 genotypes, and the coadministered antiepileptic drugs. The final model of ZNS apparent clearance was as follows: CL = 1.22 x (BW/44)0.77 x DOSE(-0.17 x 0.84CYP2C19 hetero EM x 0.70CYP2C19 PM x 1.24CBZ x 1.28PHT x 1.29PB x eetaCL where CL is the apparent oral clearance of ZNS, DOSE is ZNS daily dose, and CYP2C19 heterozygous extensive metabolizer (EM) or CYP2C19 poor metabolizer (PM) is equal to 1 if one or two CYP2C19-defective alleles are carried, respectively; otherwise, it is 0. Carbamazepine (CBZ), phenytoin (PHT), or phenobarbital (PB) is equal to 1 if carbamazepine, phenytoin, or phenobarbital is coadministered, respectively; otherwise, it is 0. etaCL is the independent random error distributed normally with the mean zero and variance equal to omegaCL. The CL of ZNS was lower in the CYP2C19 heterozygous extensive metabolizers and poor metabolizers than in the homozygous extensive metabolizers by 16% and 30%, respectively (P < 0.001). An effect of CYP3A5 polymorphisms was not identified. The coadministration of carbamazepine, phenytoin, or phenobarbital increased the CL of ZNS by 24% to 29%. This report demonstrates that the CYP2C19 genotype affects the ZNS metabolism in Japanese epileptic subjects. The clinical relevance of these changes remains to be explored in future studies.