Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

UDP-glucuronosyltransferase (UGT) metabolizes a number of endogenous and exogenous substrates. Renal cells express high amounts of UGT; however, the significance of UGT in patients with renal cell carcinoma (RCC) remains unknown. In this study, we profile the mRNA expression of UGT subtypes (UGT1A6, UGT1A9, and UGT2B7) and their genetic variants in the kidney tissue of 125 Japanese patients with RCC (Okayama University Hospital, Japan). In addition, we elucidate the association between the UGT variants and UGT mRNA expression levels and clinical outcomes in these patients. The three representative genetic variants, namely, UGT1A6 541A > G, UGT1A9 i399C > T, and UGT2B7-161C > T, were genotyped, and their mRNA expression levels in each tissue were determined. We found that the mRNA expression of the three UGTs (UGT1A6, UGT1A9, and UGT2B7) are significantly downregulated in RCC tissues. Moreover, in patients with RCC, the UGT2B7-161C > T variant and high UGT2B7 mRNA expression are significantly correlated with preferable cancer-specific survival (CSS) and overall survival (OS), respectively. As such, the UGT2B7-161C > T variant and UGT2B7 mRNA expression level were identified as significant independent prognostic factors of CSS and CSS/OS, respectively. Taken together, these findings indicate that UGT2B7 has a role in RCC progression and may, therefore, represent a potential prognostic biomarker for patients with RCC.

DOI： 10.1007/s11010-022-04637-4

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Authorship：Lead author,　Corresponding author   Language：Japanese   Publishing type：Research paper (scientific journal)  

Community pharmacists in Japan participate in many important clinical cases involving drug therapies. This involvement should be researched and widely publicized to promote evidence-based medicine (EBM). However, the awareness level about the establishment of clinical evidence among community pharmacists remains unknown. Therefore, this large-scale questionnaire survey was conducted among members of the Okayama Pharmaceutical Association to clarify the awareness about the establishment of clinical evidence among community pharmacists to determine the major factors affecting their awareness. Questionnaires requiring open-ended responses were developed in Google Forms. Finally, 366 valid answers were obtained and statistically analyzed based on three aspects: academic conference presentation, research article publication, and research conduct. More than 50% of the participants agreed that they must engage in the establishment of clinical evidence. However, they were unwilling to engage in it by themselves. Additionally, the awareness about the establishment of clinical evidence among participants aged <40 years, who underwent a 6-year course, and with presentation experience was greater than that among participants aged ≥40 years, who underwent a 4-year course and without presentation experience. Thus, age, course duration, and presentation experience are important factors influencing awareness about the establishment of clinical evidence. Further, >70% of the participants did not have enough time to engage in the establishment of clinical evidence, suggesting that reducing workload and ensuring adequate time are necessary for such engagements. Our novel findings may increase the establishment of clinical evidence by community pharmacists, improve community pharmacists' social standing, and promote EBM in Japan.

DOI： 10.1248/yakushi.22-00151

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Publishing type：Research paper (scientific journal)  

Background: It is unclear whether use of a proton pump inhibitors (PPIs) increases the risk of rhabdomyolysis. Objective: To clarify whether use of PPIs increases the risk of rhabdomyolysis. Methods: This cross-sectional study analyzed data entered into the Medical Data Vision (MDV) database in Japan and into the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). The MDV data were analyzed to evaluate the association between use of PPIs and rhabdomyolysis. Then, the FAERS data were analyzed to evaluate whether the risk of rhabdomyolysis was increased further when a statin or fibrate was used concomitantly with a PPI. In both analyses, histamine-2 receptor antagonist was set as a comparator because it is used to treat gastric disease. In the MDV analysis, Fisher’s exact test and multiple logistic regression analysis were performed. In the FAERS analysis, a disproportionality analysis using Fisher’s exact test and multiple logistic regression analysis were performed. Results: Multiple logistic regression analysis of both databases showed a significant association between use of PPIs and an increased risk of rhabdomyolysis (odds ratio [OR] = 1.74-1.95, P ≤ 0.01). However, use of a histamine-2 receptor antagonist was not significantly associated with increased risk of rhabdomyolysis. In the sub-analysis of the FAERS data, use of a PPI did not increase the risk of rhabdomyolysis in patients receiving a statin. Conclusion and Relevance: The data in 2 separate databases consistently suggest that PPIs may increase the risk of rhabdomyolysis. The evidence for this association should be assessed in further drug safety studies.

DOI： 10.1177/10600280231156270

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND/AIM: This study aimed to elucidate the detailed characteristics of CYP3A5 expression and the association between CYP3A5 expression and clinical outcomes in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: This study retrospectively enrolled 124 Japanese patients with RCC treated at the Okayama University Hospital. The commonest CYP3A5 gene polymorphism, CYP3A5*3, and expression levels of CYP3A5 mRNA and protein in each tissue were examined. RESULTS: Expression of CYP3A5 mRNA and protein in RCC tissues was significantly down-regulated compared to that in adjacent normal tissues. High level of CYP3A5 mRNA expression significantly extended cancer-specific survival (p=0.004) and overall survival (p=0.002). The CYP3A5 mRNA expression level was identified as a significant independent prognostic factor for both cancer-specific survival and overall survival. CONCLUSION: CYP3A5 could serve as a potential marker for prognostication and treatment planning for patients with RCC.

DOI： 10.21873/anticanres.15029

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Language：English   Publishing type：Research paper (scientific journal)  

We evaluated the impact of vonoprazan on blood concentrations of tacrolimus via a retrospective analysis of 52 renal transplant recipients who took tacrolimus and converted from rabeprazole to vonoprazan between August 2018 and September 2019. We compared tacrolimus trough levels upon conversion among groups that were classified based on cytochrome P450 (CYP) gene polymorphisms. CYP3A5 groups were heterozygous or homozygous for CYP3A5∗1 and CYP3A5∗3 alleles. CYP2C19 genotypes were classified as extensive (∗1/∗1), intermediate (∗1/∗2 and ∗1/∗3) or poor metabolizers (∗2/∗2, ∗2/∗3 and ∗3/∗3). Tacrolimus trough levels increased only 0.3 ng/mL upon conversion in the CYP3A5∗3/∗3 group: 5.8 [3.4-7.2] vs 6.1 [3.8-7.9]; p = 0.06. No statistically significance changes in tacrolimus levels also occurred in the CYP3A5∗1/∗1 or CYP3A5∗1/∗3 groups. Subgroup analyses of CYP3A5∗3/∗3 demonstrated low changes for all three CYP2C19 subgroups: 5.2 [4.3-6.5] vs 6.2 [4.3-7.9]; p = 0.07, 6.1 [3.4-7.2] vs 6.7 [4.6-7.9]; p = 0.12 and 5.4 [3.6-6.5] vs 4.7 [3.8-6.3]; p = 1.00, respectively. Conversion to vonoprazan thus resulted in little increase of tacrolimus trough levels, even in the group predicted to be most susceptible (CYP3A5∗3/∗3 and 2C19∗1/∗1), thus supporting the safety of concomitant use of vonoprazan with tacrolimus.

DOI： 10.1016/j.dmpk.2021.100407

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

Direct-acting antivirals, asunaprevir (ASV), daclatasvir (DCV), and beclabuvir (BCV) are known to be mainly metabolized by CYP3A enzymes; however, the differences in the detailed metabolic activities of CYP3A4 and CYP3A5 on these drugs are not well clarified. The aim of the present study was to elucidate the relative contributions of CYP3A4 and CYP3A5 to the metabolism of ASV, DCV, and BCV, as well as the effect of CYP3A5*3 genetic variant in vitro. The amount of each drug and their major metabolites were determined using LC-MS/MS. Recombinant CYP3As and CYP3A5*3-genotyped human liver microsomes (CYP3A5 expressers or non-expressers) were used for the determination of their metabolic activities. The contribution of CYP3A5 to ASV metabolism was considerable compared to that of CYP3A4. Consistently, ASV metabolic activity in CYP3A5 expressers was higher than those in CYP3A5 non-expresser. Moreover, CYP3A5 expression level was significantly correlated with ASV metabolism. In contrast, these observations were not found in DCV and BCV metabolism. To our knowledge, this is the first study to directly demonstrate the effect of CYP3A5*3 genetic variants on the metabolism of ASV. The findings of the present study may provide basic information on ASV, DCV, and BCV metabolisms.

DOI： 10.1038/s10038-019-0685-2

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Language：Japanese   Publisher：(一社)日本医学教育学会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00050&link_issn=&doc_id=20201106070007&doc_link_id=%2Fed9jmded%2F2020%2F005105%2F008%2F0541-0543%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fed9jmded%2F2020%2F005105%2F008%2F0541-0543%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Paritaprevir (PTV) is a non-structural protein 3/4A protease inhibitor developed for the treatment of hepatitis C disease as a fixed dose combination of ombitasvir (OBV) and ritonavir (RTV) with or without dasabuvir. The aim of this study was to evaluate the effects of cytochrome P450 (CYP) 3A5 on in vitro PTV metabolism using human recombinant CYP3A4, CYP3A5 (rCYP3A4, rCYP3A5) and human liver microsomes (HLMs) genotyped as either CYP3A5*1/*1, CYP3A5*1/*3 or CYP3A5*3/*3. The intrinsic clearance (CLint, Vmax/Km) for the production of a metabolite from PTV in rCYP3A4 was 1.5 times higher than that in rCYP3A5. The PTV metabolism in CYP3A5*1/*1 and CYP3A5*1/*3 HLMs expressing CYP3A5 was comparable to that in CYP3A5*3/*3 HLMs, which lack CYP3A5. CYP3A4 expression level was significantly correlated with PTV disappearance rate and metabolite formation. In contrast, there was no such correlation found for CYP3A5 expression level. This study represents that the major CYP isoform involved in PTV metabolism is CYP3A4, with CYP3A5 having a minor role in PTV metabolism. The findings of the present study may provide foundational information on PTV metabolism, and may further support dosing practices in HCV-infected patients prescribed PTV-based therapy.

DOI： 10.1080/00498254.2018.1524947

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Authorship：Lead author   Language：English  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (bulletin of university, research institution)   Publisher：国際医療福祉大学学会  

Sofosbuvir(SOF)は、C型肝炎ウイルスの増殖を阻害するヌクレオチドアナログ薬である。本研究において、我々は、水溶液およびヒト血漿中SOF濃度の簡便、特異的、高感度および精密なUV検出を用いた高速クロマトグラフィー法による測定方法の確立を試みた。0.25mLの水溶液またはヒト血漿からアセトニトリルを含む抽出液で抽出し、C18逆相カラムを用いて分析した。ソラフェニブを内標準物質(IS)とし、移動相は酢酸アンモニウム緩衝液、メタノールおよびアセトニトリルを用いた。流速は1.0mL/min、UV検出波長は265nmとした。SOFとISの検出時間はそれぞれ7.8minおよび9.1min、1検体の測定時間は15.0minであった。検量線は、0.1-10.0μg/mLの範囲で直線性を得た。それぞれの検出限界は0.1μg/mL、ヒト血漿試料からの回収率は99%以上であった。水溶液およびヒト血漿中の日内、日間変動係数はそれぞれ1.41-10.06%および0.21-6.53%であった。日内、日間精度はそれぞれ92.71-98.41%および89.31-101.21%であった。本方法は、非常に簡便でかつ試料から良好な回収が可能でありSOFの薬物動態研究を行うために用いることができる。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J05958&link_issn=&doc_id=20180426420014&doc_link_id=http%3A%2F%2Fid.nii.ac.jp%2F1065%2F00000857%2F&url=http%3A%2F%2Fid.nii.ac.jp%2F1065%2F00000857%2F&type=%8D%91%8D%DB%88%E3%97%C3%95%9F%8E%83%91%E5%8Aw%81F%8D%91%8D%DB%88%E3%97%C3%95%9F%8E%83%91%E5%8Aw%83%8A%83%7C%83W%83g%83%8A&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F80077_3.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：PHARMACEUTICAL SOC JAPAN  

Linezolid (LZD) is an antimicrobial that is commonly used for treatment of vancomycin-resistant Enterococci and methicillin-resistant Staphylococcus aureus infections. However, the development of thrombocytopenia, one of the most frequent adverse side effects of this antimicrobial, can lead to discontinuation of LZD treatment. While clinical studies indicate that risk factors for the development of LZD-induced thrombocytopenia include treatment for &gt;14 consecutive days, renal dysfunction, and chronic liver disease, the fundamental mechanism governing the pathogenesis of this disorder remains unclear. In this study, we aimed to elucidate the mechanism of LZD-induced thrombocytopenia by investigating the impact of LZD treatment on platelet destruction and production using rat platelet-rich plasma (PRP) and human immortalized cell lines, respectively. Compared to the control population, an increase in lactate dehydrogenase release was not detected upon exposure of rat PRP to varying concentrations of LZD, indicating that this compound is not cytotoxic towards platelets. Meanwhile, LZD treatment resulted in a significant dose-dependent increase in the proliferation of HEL human erythroleukemia and MEG-01 human megakaryoblast cells in vitro, but did not influence the differentiation of these cell lines. Lastly, LZD treatment yielded elevated levels of phosphorylation of myosin light chain 2 (MLC2), which regulates platelet release, in MEG-01 cells. Based on these results, we speculate that LZD induces thrombocytopenia by promoting MLC2 phosphorylation and thereby suppressing the release of platelets from mature megakaryocytes. These findings provide the first insight into the mechanism of LZD-mediated thrombocytopenia and may facilitate the development of strategies to treat and/or prevent this disease.

DOI： 10.1248/bpb.b16-00427

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：JAPANESE SOC STUDY XENOBIOTICS  

Estrone-3-sulfate (E1S) is thought to be a major estrogen precursor in estrogen receptor (ER)-positive breast cancer. Since E1S is a hydrophilic compound, the uptake of E1S into cancer cells is probably mediated by transporters, such as organic anion-transporting polypeptide (OATP, SLCO) family. In this study, we investigated the relationship between expression of OATP2B1 and cell proliferation in ER-positive breast cancer. Cell-based assays were carried out in MCF-7 cells both with and without overexpression of OATP2B1. Normal breast and tumor tissues were collected and used in this study. Cell proliferation, ER-mediated transcriptional activities and estradiol secretion were stimulated by addition of E1S to the culture medium of MCF-7 cells. These stimulatory effects were significantly greater in MCF-7 cells overexpressing OATP2B1 than in control cells. The expression level of SLCO2B1 mRNA was significantly correlated with histological grade, Ki-67 labelling index and mRNA expression of steroid sulfatase. The expression level of SLCO2B1 mRNA in luminal B-like cancers was higher than that in luminal A-like cancers. Uptake of E1S resulted in down-regulation of ER alpha protein and induction of Ki-67 in MCF-7 cells. The present study suggests that OATP2B1 is involved in cell proliferation by increasing the amount of estrogen in ER-positive breast cancer cells. Copyright (C) 2014, The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.dmpk.2014.10.005

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Drug Informatics  

Objective: In this study, we evaluated the change in degree of recognition and understanding of palliative care as pharmacy students' years advanced.<br>Methods: A questionnaire survey consisting of 11 items about recognition of narcotics and 27 items about understanding of palliative care was conducted with first- to fifth-year pharmacy students.  We divided the questions about the image of narcotics into groups and classified the questions about their knowledge of palliative care into the categories based on some reports.<br>Results: Among the three groups of questions about the image of narcotics, the degree of "right recognition of narcotics" increased, and those of "wrong recognition of narcotics" and "sense of resistance to narcotics" decreased as pharmacy students' years advanced.  Additionally, questions about their knowledge of palliative care were categorized into three: "basic guidelines for cancer pain relief and methods of narcotic use," "role of pharmacists in palliative care and support for patients," and "pharmacologic characteristics of narcotics."  Their degree of understanding of each category increased with an increase in years.  Both the recognition of narcotics and understanding of palliative care changed in the fourth- and fifth-grade year students compared to the first-, second-, and third-year ones.<br>Conclusion: These results suggest that the recognition and understanding of palliative care changed along the same trends as pharmacy students' years advanced.  Therefore, it is important that pharmacy students acquire appropriate knowledge to play an active role in palliative care.

DOI： 10.11256/jjdi.17.100

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Other Link： http://search.jamas.or.jp/link/ui/2016092766

Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Steroid sulfatase (STS) is an enzyme that hydrolyzes steroid sulfates such as dehydroepiandrosterone sulfate (DHEA-S) and estrone sulfate. STS has a key role in the synthesis of steroid hormones in placenta and breast cancer cells. Recently, we have identified six novel single-nucleotide polymorphisms (SNPs) and one nonsynonymous SNP (V476M) in the STS gene in a Japanese population. To clarify the effects of SNPs in the 5'-flanking region or 5' untranslated region on transcriptional activity, a reporter gene assay was conducted. In addition, DHEA-S desulfatase activity of a variant (Met at codon 476)-type enzyme was compared with that of the wild (Wd)-type enzyme in COS-1 cells. The transcriptional activities were significantly decreased (155A) and increased (-2837A and -1588C) in MCF-7 cells. On the other hand, no significant difference was found in expression levels of STS protein or specific activities of DHEA-S desulfation between Wd and the variant enzymes. This is the first report on the effects of various SNPs in the STS gene detected in Japanese healthy subjects.

DOI： 10.1038/jhg.2013.12

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for the Study of Xenobiotics  

It is known that rare but severe cutaneous adverse drug reactions (cADRs), such as Stevens- Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS), are induced by carbamazepine (CBZ). Recent studies have shown an association between HLAA* 31:01 and CBZ-induced severe cADRs in Japanese and Caucasian populations. In this study, we developed a simple method to detect the HLA-A*31:01 allele by nested allele-specific primer-polymerase chain reaction combined with restriction fragment length polymorphism analysis. Accuracy of the developed method was evaluated by direct sequencing analysis of PCR products amplified from DNA samples with known HLA-A genotypes and by consigning diagnosis of DNA samples with unknown HLA-A genotypes to a company providing clinical laboratory testing. The method developed in this study is simple, rapid, and of low cost compared to outsourcing tests and may be useful for in-house testing of the HLA-A*31:01 allele. © 2013 by the Japanese Society for the Study of Xenobiotics (JSSX).

DOI： 10.2133/dmpk.DMPK-12-NT-136

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society for the Study of Xenobiotics  

Steroid sulfatase (STS) is a microsomal enzyme responsible for the formation of 3β-hydroxysteroid from the corresponding sulfate conjugates. Screening of all exons, exon-intron boundaries and the 5'-flanking region of the STS gene in 93 healthy Japanese individuals was carried out. Among seven single nucleotide polymorphisms (SNPs) identified in this study, six were novel, including one in the untranslated region of exon 1, one in exon 10, and four in the 5'-flanking region. The nonsynonymous SNP (1647G&gt
A) in exon 10 caused amino-acid replacement, Val476Met, with a frequency of 0.014. The allele frequencies of the other SNPs were 0.071 for 155G&gt
A, 0.007 for -21G&gt
A, 0.014 for -1117T&gt
C, 0.106 for -1588G&gt
A, 0.007 for -2427G&gt
A and 0.007 for -2837T&gt
C.

DOI： 10.2133/dmpk.DMPK-10-SC-027

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Language：Japanese   Publisher：国際医療福祉大学学会  

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Language：Japanese   Publisher：国際医療福祉大学学会  

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：Japanese   Publisher：国際医療福祉大学学会  

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Language：Japanese   Publisher：国際医療福祉大学学会  

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Language：Japanese   Publisher：国際医療福祉大学学会  

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：Japanese   Publisher：国際医療福祉大学学会  

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Language：Japanese   Publisher：国際医療福祉大学学会  

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：INFORMA HEALTHCARE  

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Language：Japanese   Publisher：国際医療福祉大学学会  

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Language：Japanese   Publisher：日本地域薬局薬学会  

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