Drug Metabolism and Pharmacokinetics最新文献_第3页

Impact of degradation in subcutaneous tissue and lymphatic fluid on absorption of Fc-fusion proteins following subcutaneous administration 皮下给药后皮下组织和淋巴液降解对fc融合蛋白吸收的影响

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-10-01 Epub Date: 2025-07-17 DOI: 10.1016/j.dmpk.2025.101500

Miki Yokoyama, Eiko Suzuki, Daisuke Nakai

{"title":"Impact of degradation in subcutaneous tissue and lymphatic fluid on absorption of Fc-fusion proteins following subcutaneous administration","authors":"Miki Yokoyama, Eiko Suzuki, Daisuke Nakai","doi":"10.1016/j.dmpk.2025.101500","DOIUrl":"10.1016/j.dmpk.2025.101500","url":null,"abstract":"<div><div>Subcutaneous administration is widely used as a clinical administration route for Fc-fusion proteins. However, predicting bioavailability (BA) in humans after subcutaneous administration is challenging due to multiple factors involved in the absorption process. This study aimed to elucidate the impact of degradation on the BA of Fc-fusion proteins. We established two measurement methods for each Fc-fusion protein: the Fc/Fc method, which recognizes the Fc region; and the Protein/Fc method, which recognizes both protein and Fc region. BA of dulaglutide and romiplostim in rats were 80.1 % and 99.4 % by the Fc/Fc method, and 35.0 % and 55.5 % by the Protein/Fc method, respectively. The lower BA with the Protein/Fc method indicates that the protein region undergoes degradation during the absorption process. In stability studies with rat skin homogenates and lymphatic fluid, degradation of the protein region for both dulaglutide and romiplostim was confirmed, which was inhibited by protease inhibitors. In contrast, abatacept and etanercept were stable in skin homogenates and lymphatic fluid, and their BA in rats were comparable between the Fc/Fc and Protein/Fc methods. This study indicates that the presence or absence of protease-mediated degradation during the absorption process is one of the factors affecting the BA of Fc-fusion proteins.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"64 ","pages":"Article 101500"},"PeriodicalIF":2.2,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144988521","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

Construction of refined CYP2D6-Template system for studies of its metabolism and inhibition 精制cyp2d6 -模板体系的构建及其代谢和抑制研究

IF 2.2 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-08-01 Epub Date: 2025-07-02 DOI: 10.1016/j.dmpk.2025.101499

Yasushi Yamazoe , Norie Murayama , Kouichi Yoshinari

{"title":"Construction of refined CYP2D6-Template system for studies of its metabolism and inhibition","authors":"Yasushi Yamazoe , Norie Murayama , Kouichi Yoshinari","doi":"10.1016/j.dmpk.2025.101499","DOIUrl":"10.1016/j.dmpk.2025.101499","url":null,"abstract":"<div><div>The previously reported Template system for the prediction of human CYP2D6-mediated reactions (Drug Metab Dispos 40 486-96, 2012) has been refined with the introduction of ideas of allowable width, Trigger∗-residue and the residue-initiated movement of ligands in the active site. These ideas are in common with published Template systems for human CYP1A1, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2E1, CYP2J2, and CYP3A4/5/7 (Drug Metab Pharmacokinet 2016, 2019, 2020, 2021, 2022, 2023, and 2024, Food Safety 2024). Total 616 reactions of 441 distinct chemicals reported as CYP2D6 ligands were examined in the refined CYP2D6-Template system. From their placements on the refined Template and rules for interaction modes, verifications of good and poor substrates, regio/stereo-selectivity, and inhibition became faithfully available for these ligands. A comparison of the placements suggested key interactions with Shelf and Left-end for ligand accommodations on the refined CYP2D6-Template. Shelf-surrounding of ligands was also proposed as a cause of their intense inhibitions. The refined CYP2D6-Template system will thus offer reliable estimations of this human CYP catalyses toward ligands of diverse structures, together with their deciphering information to lead to judgments of regioselective metabolisms.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"63 ","pages":"Article 101499"},"PeriodicalIF":2.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144842811","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

Investigation of an OATP1B inhibitory effect by a cyclic peptide using the endogenous biomarker coproporphyrin-I in monkeys 利用内源性生物标志物coproporphyrin-I研究环肽对猴子OATP1B的抑制作用

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-08-01 Epub Date: 2025-06-03 DOI: 10.1016/j.dmpk.2025.101497

Hiromi Sawada , Yasuto Kido , Makoto Iwasaki , Kimiko Nishida , Kei Mayumi , Ryosuke Watari

{"title":"Investigation of an OATP1B inhibitory effect by a cyclic peptide using the endogenous biomarker coproporphyrin-I in monkeys","authors":"Hiromi Sawada , Yasuto Kido , Makoto Iwasaki , Kimiko Nishida , Kei Mayumi , Ryosuke Watari","doi":"10.1016/j.dmpk.2025.101497","DOIUrl":"10.1016/j.dmpk.2025.101497","url":null,"abstract":"<div><div>Peptide drugs are expected to be a new modality that will replace traditional small molecule drugs. As the number of approved peptide drugs increases, they are being co-administered with various drugs, but there is a limited number of reports on their drug-drug interaction (DDI) in both <em>in vitro</em> and <em>in vivo</em> (clinical) studies. In this study, we investigated the transporter inhibitory potential of Compound A, a macrocyclic peptide (3.5 kDa) for the treatment of pain. We found that Compound A exhibited a strong inhibitory effect on the organic anion transporting polypeptide (OATP) 1B in an <em>in vitro</em> study. To assess the <em>in vivo</em> OATP1B inhibitory potential, Compound A was intravenously or subcutaneously administered to monkeys, and the plasma concentration of coproporphyrin-I (CP-I), an endogenous biomarker of OATP1B, was determined. Compound A markedly increased the CP-I concentration in monkeys. A semi-mechanistic pharmacokinetic model analysis using the CP-I concentration revealed that Compound A is a highly potent <em>in vivo</em> OATP1B inhibitor (<em>in vivo</em> K<sub>i, OATP1B</sub>: 59.9 ng/mL as total plasma concentration). Our findings suggest that even peptides with a large molecular weight can cause DDI. These results offer valuable information for the further development of DDI guidelines for peptides.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"63 ","pages":"Article 101497"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144549742","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

Continuous exposure to therapeutic drugs doxorubicin and vincristine reduces drug efficacy through transcriptional and post-transcriptional regulation of P-glycoprotein in follicular lymphoma 持续暴露于治疗药物阿霉素和长春新碱通过转录和转录后调节p -糖蛋白降低滤泡性淋巴瘤的药物疗效

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-08-01 Epub Date: 2025-05-26 DOI: 10.1016/j.dmpk.2025.101495

Kentaro Yano , Yumiko Iwase , Takuo Ogihara , Takashi Kuwabara

{"title":"Continuous exposure to therapeutic drugs doxorubicin and vincristine reduces drug efficacy through transcriptional and post-transcriptional regulation of P-glycoprotein in follicular lymphoma","authors":"Kentaro Yano , Yumiko Iwase , Takuo Ogihara , Takashi Kuwabara","doi":"10.1016/j.dmpk.2025.101495","DOIUrl":"10.1016/j.dmpk.2025.101495","url":null,"abstract":"<div><div>Resistance to drugs used at the onset of follicular lymphoma could develop after continued drug treatment or at the time of recurrence. Therefore, we investigated how the continuous exposure to therapeutic drugs affects P-gp and drug resistance using follicular lymphoma cells. The mRNA expression levels of P-gp in Sci-1 cells treated with Dox or Dox + Vinc were increased. The increase in protein levels was consistent with the behavior of mRNA. The efflux clearance of Rho123 in Sci-1 cells exposed to Dox or Dox + Vinc was significantly increased. In cells continuously exposed to Dox or Dox + Vinc, a significant increase in the IC50 of Dox and an inhibitory effect of Vera on this increase were observed. It has been revealed that therapeutic drugs for follicular lymphoma, such as Dox or Dox + Vinc, increase the expression level of P-gp at the transcriptional level. The transport function of P-gp and drug resistance were enhanced depending on the increase in the amount of P-gp expressed on the membrane. Consequently, our results suggested that continuous exposure to clinical blood levels of Dox + Vinc can significantly affect drug resistance in follicular lymphoma by enhancing P-gp function through transcriptional and post-transcriptional regulation.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"63 ","pages":"Article 101495"},"PeriodicalIF":2.7,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144510963","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 assessment of immortalized human brain microvascular endothelial cells with different passage numbers: A case study for a prospective proposal on variability management of in vitro blood-brain barrier models 不同传代数的永生化人脑微血管内皮细胞的功能评估：体外血脑屏障模型变异性管理前瞻性建议的案例研究

IF 2.7 4区医学

Drug Metabolism and Pharmacokinetics Pub Date : 2025-06-01 Epub Date: 2025-02-20 DOI: 10.1016/j.dmpk.2025.101058

Seiya Ohki , Mei Fukuda , Tomoyo Baba , Naomi Wakayama , Hanae Morio , Shingo Ito , Sumio Ohtsuki , Yoshiyuki Yamaura , Takafumi Komori , Tomomi Furihata

{"title":"Functional assessment of immortalized human brain microvascular endothelial cells with different passage numbers: A case study for a prospective proposal on variability management of in vitro blood-brain barrier models","authors":"Seiya Ohki , Mei Fukuda , Tomoyo Baba , Naomi Wakayama , Hanae Morio , Shingo Ito , Sumio Ohtsuki , Yoshiyuki Yamaura , Takafumi Komori , Tomomi Furihata","doi":"10.1016/j.dmpk.2025.101058","DOIUrl":"10.1016/j.dmpk.2025.101058","url":null,"abstract":"<div><div><em>In vitro</em> blood-brain barrier (BBB) models, primarily consisting of brain microvascular endothelial cells (BMEC), are expected to play pivotal roles in evaluating drug permeability into the brain. However, these models often exhibit functional variability due to various factors, raising practical concerns that can hinder their use in drug development studies. By investigating cell passage numbers as one such factor, we aim to assess how BBB model functionality is affected and to propose a practical strategy for managing this variability. In transwell-BBB models - but not in spheroidal-BBB models - the intercellular barrier integrity was somewhat compromised when higher-passage human immortalized BMEC (HBMEC/ci18) were used. Nonetheless, a clear <em>in vitro-in vivo</em> correlation (IVIVC) curve could still be obtained with these transwell-BBB models, similar to those with lower passage number HBMEC/ci18, presumably allowing for reasonable estimation of <em>in vivo</em> drug permeability. Therefore, changes in functional levels of BBB models do not always significantly diminish their practical value in drug BBB permeability studies. Additionally, the IVIVC curve integrity may serve as an indicator for assessing acceptable BBB model functionality. These findings provide valuable insights for the future application of <em>in vitro</em> human BBB models in drug development studies.</div></div>","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"62 ","pages":"Article 101058"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143760690","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

Development of an in vitro Metabolic Dysfunction-Associated Steatohepatitis (MASH) model to study hepatic transporters 建立体外代谢功能障碍相关脂肪性肝炎（MASH）模型研究肝脏转运体

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.2025.101123

Sarina Kyburz , William A. Murphy , Thomas Kralj , John K. Fallon , Jacqueline B. Tiley , Kim L.R. Brouwer

引用次数: 0

Novel mechanisms of drug-metabolizing hydrolases regulating the toxicity caused by reactive metabolites 药物代谢水解酶调节活性代谢物毒性的新机制

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.2025.101066

Tatsuki Fukami

引用次数: 0

Development and qualification of an in vitro assay to determine target mediated internalization of TREM2 receptor specific antibodies for TMDD assessment 开发和鉴定用于TMDD评估的TREM2受体特异性抗体靶介导内化的体外测定方法

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.2025.101134

Thomas Kraft , Anna-Lena Bolender , Aman Padamsey , Erich Koller , Markus Britschgi , Jens Niewoehner , Hans Peter Grimm

引用次数: 0

Evaluation for biotransformation of antibody-peptide conjugates using native mass spectrometry 利用天然质谱法评价抗体-肽偶联物的生物转化

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.2025.101135

Hiraku Hagita, Sahana Iwamura, Tomoki Suzuki, Kenichi Sasahara, Keisuke Maki, Yosuke Kaneko

引用次数: 0

Bioanlaysis, biotransformation and pharmacokinetics of antibody-drug conjugate 抗体-药物偶联物的生物分析、生物转化和药代动力学

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.2025.101074

Yuki Kishino

引用次数: 0