Drug Metabolism and Pharmacokinetics最新文献_第5页

Mitigating strategy for drug induced liver injury LED by reactive metabolites 反应性代谢物对药物性肝损伤的缓解策略

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2025-06-03 DOI: 10.1016/j.dmpk.2025.101065

Sean Zhu

引用次数: 0

Converting suspension-type human primary hepatocytes to be plateable-type for use as an in vitro pharmacokinetics model 将悬浮型人原代肝细胞转化为血小板型，用于体外药代动力学模型

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2024-12-04 DOI: 10.1016/j.dmpk.2024.101044

Raghda Shahin , Yoko Sakai , Kotaro Shirai , Tadahiro Hashita , Tamihide Matsunaga , Takahiro Iwao

{"title":"Converting suspension-type human primary hepatocytes to be plateable-type for use as an in vitro pharmacokinetics model","authors":"Raghda Shahin , Yoko Sakai , Kotaro Shirai , Tadahiro Hashita , Tamihide Matsunaga , Takahiro Iwao","doi":"10.1016/j.dmpk.2024.101044","DOIUrl":"10.1016/j.dmpk.2024.101044","url":null,"abstract":"<div><div>Preclinical animal models cannot precisely predict medication failures in clinical trials. Human primary hepatocytes (HPHs) are the gold standard for <em>in vitro</em> culture systems that recapitulate <em>in vivo</em> human liver characteristics. Consequently, demand for HPHs is rising despite their high cost, batch-to-batch variability, and inadequate supply. Existing commercial HPHs are plateable (pHPHs) and suspension (sHPHs) using same isolation and cryopreservation technique. The sHPHs cannot be cultured on the plate surface or cannot efficiently relocalize efflux transporters. They can also have a life of maximum of 2–4 h. Therefore, they are unsuitable for assays requiring well-organized efflux transporters or long-term studies, such as enzyme induction or metabolic assays for low-turnover drugs. We aim to develop a novel pharmacokinetic model of converted sHPHs to be attached like pHPHs. We successfully cultured sHPHs as 2D sandwich-cultured sHPHs for use as a promising, reproducible, and affordable <em>in vitro</em> model for efflux trans-porter assays, cytochrome P450 induction, and metabolic studies. The sHPHs successfully attached, converted to be plateable, similar morphology, and mRNA expression as pHPHs, as well as detectable metabolic activity and extended lifespan. Overall, this study is the first to culture functional 2D sandwich sHPHs as a novel <em>in vitro</em> pharmacokinetic model.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"62 ","pages":"Article 101044"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941145","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gastrointestinal imaging with MRI: Insights into the behavior of dosage forms and the conditions at the site of drug release 胃肠道成像与MRI：洞察剂量形式的行为和药物释放部位的条件

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2025-06-03 DOI: 10.1016/j.dmpk.2025.101069

Werner Weitschies

引用次数: 0

TOC TOC

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2025-06-03 DOI: 10.1016/S1347-4367(25)00438-0

引用次数: 0

Buffer compositions strongly impact the in vitro assessment of CYP fraction metabolized using human liver microsomes or expressed isoenzymes 缓冲成分强烈影响体外评估使用人肝微粒体或表达的同工酶代谢的CYP部分

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2025-03-14 DOI: 10.1016/j.dmpk.2025.101480

Yuta Tamemoto , Yukihiro Shibata , Natsumi Hashimoto , Aoi Yoshitomo , Shizuka Hozuki , Keita Takahashi , Hana Kumemura , Hiroto Hatakeyama , Hiromi Sato , Akihiro Hisaka

{"title":"Buffer compositions strongly impact the in vitro assessment of CYP fraction metabolized using human liver microsomes or expressed isoenzymes","authors":"Yuta Tamemoto , Yukihiro Shibata , Natsumi Hashimoto , Aoi Yoshitomo , Shizuka Hozuki , Keita Takahashi , Hana Kumemura , Hiroto Hatakeyama , Hiromi Sato , Akihiro Hisaka","doi":"10.1016/j.dmpk.2025.101480","DOIUrl":"10.1016/j.dmpk.2025.101480","url":null,"abstract":"<div><div>We systematically evaluated the effects of different buffer compositions on the activities of cytochrome P450 (CYP)1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, and CYP3A in human liver microsomes and in recombinant human CYP expression systems using the <em>in vitro</em> cocktail method. The activities of all CYP isoenzymes varied depending on the buffer conditions, particularly the activity of CYP1A2, which varied by 27.0-fold in phosphate buffer and HEPES or Tris-HCl buffer. The difference in the metabolic activities of CYP2D6 and CYP3A4 was smaller but significant, showing values about 2.0- and 3.0-fold higher in phosphate buffer than in HEPES or Tris-HCl buffer. A similar trend was observed for recombinant human CYP3A4/5. In contrast, the metabolic activities of CYP2A6 and CYP2B6 in phosphate buffer decreased by less than half as the phosphate concentration was increased. Changes in the metabolic activity of multiple CYP isoenzymes in buffers with different compositions suggest that the fraction metabolized (fm) evaluated <em>in vitro</em> differs depending on the experimental conditions. Specifically, the previously reported fm values of CYP1A2, CYP2B6, CYP2D6, and CYP3A in phosphate buffer may be overestimated. When evaluating the fm of these isoenzymes, we recommend conducting experiments under multiple buffer conditions.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"62 ","pages":"Article 101480"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143923638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Functional characteristics of equilibrative nucleoside transporter 2 (ENT2/SLC29A2) for the transport of urate as a newly identified substrate 平衡核苷转运蛋白2 （ENT2/SLC29A2）作为新发现的底物运输尿酸盐的功能特征

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2024-12-28 DOI: 10.1016/j.dmpk.2024.101048

Isamu Matake , Tomoya Yasujima , Hirotaka Matsuo , Yu Toyoda , Yusuke Kawamura , Tappei Takada , Katsuhisa Inoue , Takahiro Yamashiro , Hiroaki Yuasa

{"title":"Functional characteristics of equilibrative nucleoside transporter 2 (ENT2/SLC29A2) for the transport of urate as a newly identified substrate","authors":"Isamu Matake , Tomoya Yasujima , Hirotaka Matsuo , Yu Toyoda , Yusuke Kawamura , Tappei Takada , Katsuhisa Inoue , Takahiro Yamashiro , Hiroaki Yuasa","doi":"10.1016/j.dmpk.2024.101048","DOIUrl":"10.1016/j.dmpk.2024.101048","url":null,"abstract":"<div><div>Equilibrative nucleoside transporters (ENTs) are known to be involved in the membrane transport of nucleosides and nucleobases. We here report our finding that ENT2/SLC29A2 can also transport urate, which is the final metabolite of purine nucleobases. In transiently transfected human embryonic kidney 293 (HEK293) cells, urate uptake by human ENT2 was quite efficient at an acidic pH of 5.5, being saturable with the <em>K</em><sub>m</sub> of 1.64 mM and inhibited by its nucleoside substrates and specific inhibitors. Although the uptake activity decreased with increasing pH, it was still detected at around near neutral pH. In the Caco-2 cell model, urate uptake was reduced by ENT2 inhibitors and by ENT2 knockdown, indicating the involvement of ENT2 in urate transport. In HEK293 cells transiently transfected with sodium-dependent nucleobase transporter 1, which can accumulate urate, urate uptake was reduced by cotransfection of ENT2, suggesting its operation for urate efflux. Interestingly, ENT2 with N68K mutation was found to have little urate uptake activity, whereas the urate efflux activity was maintained. This finding suggests that ENT2 may operate in different modes for the uptake and efflux of urate. Overall, this study provides novel insight into the function of ENT2 and its potential role in urate disposition.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"62 ","pages":"Article 101048"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143941144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Improving ADME properties of therapeutic antibodies by novel engineering technologies 利用新的工程技术改善治疗性抗体的ADME特性

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2025-06-03 DOI: 10.1016/j.dmpk.2025.101086

Kenta Haraya

引用次数: 0

Does cannabidiol (CBD) or delta-9-tetrahydrocannabinol (THC) induce drug metabolizing enzymes in human hepatocytes? 大麻二酚（CBD）或德尔塔-9-四氢大麻酚（THC）诱导人肝细胞药物代谢酶吗？

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2025-06-03 DOI: 10.1016/j.dmpk.2025.101126

Ankit Balhara, Yik Pui Tsang, Jashvant D. Unadkat

引用次数: 0

Implementation of blood collection using the Tasso microsampling device to measure thyroid hormone biomarkers 利用Tasso微采样装置采集血液，测量甲状腺激素生物标志物