Masaki Matsuura

Allele and genotype frequencies of CYP2B6 and CYP3A5 in the Japanese population.

HeadingAbstractObjective. The goal of this study was to determine the frequencies of allelic variants of CYP2B6 and CYP3A5 in the Japanese population.Methods. Genotyping of CYP2B6(*2, *3, *4, *5, *6, and *7) and CYP3A5 (*2, *3, *4, *5, and *6) was carried out in 265 unrelated Japanese subjects by polymerase chain reaction (PCR), restriction fragment length polymorphism and allele-specific, real-time PCR assays.Results. Allele frequencies for CYP2B6*2, *3, *4, *5, *6, and *7 in 256 Japanese subjects were 0.047, 0, 0.093, 0.011, 0.164, and 0, respectively. Ethnic variation in allele frequencies relative to that in Caucasian subjects was observed for CYP2B6*4 (0.093 vs 0.040), *5 (0.011 vs 0.109), *6 (0.164 vs 0.256), and *7 (0 vs 0.030). Allele frequencies for CYP3A5*2, *3, *4, *5, and *6 in 265 Japanese subjects were 0, 0.740, 0, 0.004, and 0, respectively. The frequency of the CYP3A5*1 allele is 2.8 times higher in Japanese than in Caucasians.Conclusions. Our results contribute to a better understanding of the molecular basis of ethnic differences in drug response, which may help to improve individualization of drug therapy and offer a preliminary basis for more rational use of drugs that are substrates for CYP2B6 and CYP3A5 in the Japanese population.

Transport of fluorescent chenodeoxycholic acid via the human organic anion transporters OATP1B1 and OATP1B3

This study sought to clarify the contributions of organic anion-transporting polypeptide (OATP) 1B1 and 1B3 to the liver uptake of chenodeoxycholic acid (CDCA). We synthesized a fluorescent version of CDCA, chenodeoxychilyl-(Nϵ-NBD)-lysine (CDCA-NBD), to characterize transporter-mediated uptake. CDCA-NBD is efficiently transported by OATP1B1 and OATP1B3 with high affinities. The Michaelis-Menten constants for CDCA-NBD uptake by OATP1B1 and OATP1B3 were 1.45 ± 0.39 μM and 0.54 ± 0.09 μM, respectively. By confocal laser scanning microscopy, CDCA-NBD, which is taken up by OATP1B1 and OATP1B3, was observed to localize to the cytosol. We also examined the transport of newly synthesized fluorescent bile acids. NBD-labeled bile acids, including cholic acid, deoxycholic acid, lithocholic acid, and ursodeoxycholic acid, were all transported by OATP1B1 and OATP1B3. CDCA-NBD exhibited the highest rate of transport of the five NBD-labeled bile acids examined in OATP1B1- and OATP1B3-expressing cells. Our results suggest that OATP1B1 and OATP1B3 play important roles in CDCA uptake into the liver. Fluorescent bile acids are useful tools to characterize the uptake properties of membrane transporters.

Life-event stress induced by the Great East Japan Earthquake was associated with relapse in ulcerative colitis but not Crohn's disease: a retrospective cohort study

Objective Stress is thought to be one of the triggers of relapses in patients with inflammatory bowel disease (IBD). We examined the rate of relapse in IBD patients before and after the Great East Japan Earthquake. Design A retrospective cohort study. Settings 13 hospitals in Japan. Participants 546 ulcerative colitis (UC) and 357 Crohns disease (CD) patients who received outpatient and inpatient care at 13 hospitals located in the area that were seriously damaged by the earthquake. Data on patients clinical characteristics, disease activity and deleterious effects of the earthquake were obtained from questionnaires and hospital records. Primary outcome We evaluated the relapse rate (from inactive to active) across two consecutive months before and two consecutive months after the earthquake. In this study, we defined ‘active’ as conditions with a partial Mayo score=2 or more (UC) or a Harvey-Bradshaw index=6 or more (CD). Results Among the UC patients, disease was active in 167 patients and inactive in 379 patients before the earthquake. After the earthquake, the activity scores increased significantly (p<0.0001). A total of 86 patients relapsed (relapse rate=15.8%). The relapse rate was about twice that of the corresponding period in the previous year. Among the CD patients, 86 patients had active disease and 271 had inactive disease before the earthquake. After the earthquake, the activity indices changed little. A total of 25 patients experienced a relapse (relapse rate=7%). The relapse rate did not differ from that of the corresponding period in the previous year. Multivariate analyses revealed that UC, changes in dietary oral intake and anxiety about family finances were associated with the relapse. Conclusions Life-event stress induced by the Great East Japan Earthquake was associated with relapse in UC but not CD.

A simultaneous LightCycler detection assay for five genetic polymorphisms influencing drug sensitivity.

OBJECTIVES The routine detection of polymorphisms affecting drug sensitivity in patients before treatment is important in the identification of drug responders or nonresponders, and patients at increased risk of drug toxicity. Here, we present an assay for the simultaneous and rapid genotyping of five polymorphisms influencing drug sensitivity. DESIGN AND METHODS We used a hybridization probe assay on the LightCycler to detect five single nucleotide polymorphisms (SNPs): INPP1 (973C>A), ADRB2 (R16G and Q27E), HTR2A (102T>C), and mtDNA (1555A>G). Two fluorescent labeled hybridization probes were designed for the simultaneous detection of the five SNPs and detection of the variant alleles was performed by melting curve analysis. RESULTS All five SNPs were detected with a single thermocycle protocol within 40 min. The genotypes determined in this assay were identical to those obtained with conventional PCR and restriction fragment length polymorphism analysis. CONCLUSIONS To our knowledge, we report here for the first time a method for simultaneous detection of five SNPs, on a single thermocycle protocol by the LightCycler. This method is rapid, highly sensitive, and high-throughput, and is thus suitable for routine clinical use and large-scale epidemiologic studies.

Monitoring Serum Levels of Sorafenib and Its N-Oxide Is Essential for Long-Term Sorafenib Treatment of Patients with Hepatocellular Carcinoma

Sorafenib, an oral multi-kinase inhibitor, is the final therapy prior to palliative care for advanced hepatocellular carcinoma (HCC). However, due to its adverse effects, 20% of patients must discontinue sorafenib within 1 month after first administration. To identify ways to predict the adverse effects and administer the drug for longer periods, we explored the relationship between the duration of sorafenib treatment and the pharmacokinetics of sorafenib and its major metabolite, sorafenib N-oxide. Twenty-five subjects enrolled in the study were divided into two groups: patients with dosage reduced or withdrawn due to adverse effects (n = 8), and patients with dosage maintained for 1 month after initial administration (n = 17). We evaluated early sorafenib accumulation as the area under the curve of sorafenib and sorafenib N-oxide concentrations during days 1-7 (AUC(sorafenib) and AUC(N-oxide), respectively). Inter-group comparison revealed that AUC(N-oxide) and AUC ratio (AUC(N-oxide)/AUC(sorafenib)) were significantly higher in the dosage reduction/withdrawal group (P = 0.031 and P = 0.0022, respectively). Receiver operating characteristic analysis indicated that AUC(N-oxide) and AUC ratio were reliable predictors of adverse effects. When patients were classified by cut-off points (AUC(N-oxide:) 2.0 μg ∙ day/mL, AUC ratio: 0.13), progression-free survival was significantly longer in patients with AUC(N-oxide) ≤ 2.0 μg ∙ day/mL (P = 0.0048, log-rank test). In conclusion, we recommend to simultaneously monitor serum levels of sorafenib and its N-oxide during the early stage after the first administration, which enables us to provide safe and long-term therapy for each HCC patient with sorafenib.

Knowledge of and Perspectives on Pharmacovigilance among Pharmacistsin the Miyagi and Hokkaido Regions of Japan

The aim of the present study was to clarify the knowledge of and perspectives on pharmacovigilance among pharmacists in the Miyagi and Hokkaido regions of Japan. In this cross-sectional, self-administered questionnairebased study, we contacted 3,164 pharmacists who belonged to the Miyagi Prefecture Hospital Pharmacists Association or the Hokkaido Society of Hospital Pharmacists during the 3-month period between January and March 2013. Of the 1,851 respondents (<30 years, 22.2%; ≥ 50 years, 25.8%; women, 41.9%), 6.9%, 22.1%, and 71.0% answered “I understand what it is”, “I have heard of it, but I do not understand what it is”, and “I do not know what it is”, respectively, to the question “Have you ever heard of the term ‘pharmacovigilance’?”. Multivariate logistic regression analysis revealed that being ≥ 50 years old (odds ratio [OR]: 6.10, 95% confidence interval [CI]: 1.99-18.72), having a doctoral degree (OR: 6.33; 95%CI: 3.19-12.57), and having ≥ 10 pharmacists in the workplace (OR: 2.08; 95%CI: 1.20-3.60) were ifica3.60) were significantly and independently associated with understanding “pharmacovigilance.” Pharmacists who understood “pharmacovigilance” also tended to know more related terms and actions. Furthermore, 76.2% of the respondents thought that pharmacists should be responsible for pharmacovigilance in the clinical setting, and even though most of the pharmacists in Japan had insufficient knowledge of pharmacovigilance, 71.9% wished to acquire more.

Prevalence, Determinants, and Reasons for the Non-Reporting of Adverse Drug Reactions by Pharmacists in the Miyagi and Hokkaido Regions of Japan

Little is known about the potential of adverse drug reaction (ADR) non-reporting by Japanese pharmacists. The aim of the present study was to clarify the prevalence, determinants, and reasons for ADR non-reporting by pharmacists in the Miyagi and Hokkaido regions of Japan. In this cross-sectional, self-administered questionnaire-based study, we contacted 3,164 pharmacists who belonged to the Miyagi Prefecture Hospital Pharmacists Association or the Hokkaido Society of Hospital Pharmacists during the 3-month period between January to March 2013. Of the 1,795 respondents 22.4% were <30 years of age, 25.6% were ≥ 50 years of age, and 42.1% were female. A total of 77.6% of the respondents did not have a personal history of ADR reporting. The multivariate logistic regression analysis showed that female sex (odds ratio, 1.52; 95% confidence interval, 1.17-1.97), having <10 years of practical experience (2.59, 1.39-4.82 for 5-9 years; 7.03, 2.94-16.83 for <5 years), working at a community pharmacy or drugstore (1.90, 1.16-3.12), having <5 pharmacists in the workplace (2.01, 1.48-2.75), and not understanding the ADR reporting system (5.93, 4.23-8.33) were significantly and independently associated with not having a personal history of ADR reporting. The most common reason for ADR non-reporting was “It was a well-known adverse drug reaction” (43.0%) followed by “Association between the drug and adverse reaction was not clear” (38.0%), “It was a minor adverse drug reaction” (29.0%), “Did not know how to make a report” (17.4%), and “Never been consulted about ADRs” (17.2%). As an understanding the ADR reporting system was strongly associated with ADR reporting, a more aggressive promotion of the ADR reporting system among pharmacists is warranted.

Long-term course of inflammatory bowel disease after the Great East Japan Earthquake: Long-course of IBD after the earthquake

This study analyzed inflammatory bowel disease activity for 2 years after the Great East Japan Earthquake.