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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 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-03 DOI: 10.1016/j.dmpk.2025.101497
Hiromi Sawada , Yasuto Kido , Makoto Iwasaki , Kimiko Nishida , Kei Mayumi , Ryosuke Watari
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 in vitro and in vivo (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 in vitro study. To assess the in vivo 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 in vivo OATP1B inhibitor (in vivo Ki, OATP1B: 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.
肽类药物有望成为替代传统小分子药物的一种新形态。随着批准的多肽药物数量的增加,它们正在与各种药物共同给药,但在体外和体内(临床)研究中,关于它们的药物相互作用(DDI)的报道有限。在这项研究中,我们研究了化合物A的转运蛋白抑制电位,化合物A是一种大环肽(3.5 kDa),用于治疗疼痛。我们在体外研究中发现化合物A对有机阴离子转运多肽(OATP) 1B具有较强的抑制作用。为了评估体内对OATP1B的抑制潜力,我们将化合物A静脉注射或皮下注射给猴,并测定了OATP1B内源性生物标志物co - proporphyrin- i (CP-I)的血浆浓度。化合物A显著提高了cp - 1在猴子体内的浓度。利用cp - 1浓度的半机械药代动力学模型分析显示,化合物A是一种高效的体内OATP1B抑制剂(体内Ki, OATP1B: 59.9 ng/mL作为总血浆浓度)。我们的研究结果表明,即使是分子量较大的肽也能引起DDI。这些结果为进一步制定多肽DDI指南提供了有价值的信息。
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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 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101123
Sarina Kyburz , William A. Murphy , Thomas Kralj , John K. Fallon , Jacqueline B. Tiley , Kim L.R. Brouwer
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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 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101134
Thomas Kraft , Anna-Lena Bolender , Aman Padamsey , Erich Koller , Markus Britschgi , Jens Niewoehner , Hans Peter Grimm
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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 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101135
Hiraku Hagita, Sahana Iwamura, Tomoki Suzuki, Kenichi Sasahara, Keisuke Maki, Yosuke Kaneko
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引用次数: 0
How do i build an ‘Ideal’ PBPK model if my drug is either a substrate or inducer 如果我的药物是底物或诱导剂,我如何建立一个“理想的”PBPK模型
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101061
Ryuta Asaumi
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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 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101066
Tatsuki Fukami
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引用次数: 0
Phenotyping assay using genetically manipulated human IPS cell-derived hepatocyte- like cells 利用基因操纵的人IPS细胞衍生的肝细胞样细胞进行表型分析
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101102
Hiroyuki Mizuguchi
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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 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101074
Yuki Kishino
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引用次数: 0
Botanical-drug interactions: Blazing the trail using translational tools 植物-药物相互作用:利用翻译工具开辟道路
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101116
Mary Paine
{"title":"Botanical-drug interactions: Blazing the trail using translational tools","authors":"Mary Paine","doi":"10.1016/j.dmpk.2025.101116","DOIUrl":"10.1016/j.dmpk.2025.101116","url":null,"abstract":"","PeriodicalId":11298,"journal":{"name":"Drug Metabolism and Pharmacokinetics","volume":"61 ","pages":"Article 101116"},"PeriodicalIF":2.7,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144195420","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
Discovery, validation, and application of transporter endogenous biomarkers: A work of translation 转运体内源性生物标志物的发现、验证和应用:翻译工作
IF 2.7 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2025-06-01 DOI: 10.1016/j.dmpk.2025.101093
Hong Shen
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引用次数: 0
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Drug Metabolism and Pharmacokinetics
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