三维细胞模型在肿瘤研究中的应用

三维细胞模型借助特殊材料或载体在体外培养不同种类的细胞,使细胞在三维环境中生长、迁移和分化。三维细胞模型为细胞提供接近体内生存的体外环境,使细胞的基因表达、信号传递更具生理学相关性。本文从三维细胞模型的概念与分类入手,综述了近几年三维细胞模型在肿瘤微环境、肿瘤转移与抗肿瘤药物研发的应用与进展。基于三维细胞模型目前存在的不足,对其在肿瘤治疗中的应用提出了设想与展望。     

Physiological based pharmacokinetic modeling to estimate in vivo Ki of ketoconazole on renal P-gp using human drug-drug interaction study result of fesoterodine and ketoconazole

This study was conducted to estimate in vivo inhibition constant (Ki) of ketoconazole on renal P-glycoprotein (P-gp) using human drug-drug interaction (DDI) study result of fesoterodine and ketoconazole. Fesoterodine is a prodrug which is extensively hydrolyzed by non-specific esterases to the active metabolite 5-hydroxymethyl tolterodine (5-HMT). 5-HMT is then further metabolized via Cytochrome P450 (CYP) 2D6 and CYP3A4. It is reported that 5-HMT is a substrate of P-gp whereas fesoterodine is not. Renal clearance of 5-HMT is approximately two-times greater than renal glomerular filtration rate. This suggests the possibility that renal clearance of 5-HMT involves secretion by P-gp. Utilizing the available pharmacokinetic characteristics of fesoterodine and 5-HMT, we estimated in vivo Ki of ketoconazole on P-gp at kidney based on DDI study data using physiologically-based pharmacokinetic approach. The estimated in vivo Ki of ketoconazole for hepatic CYP3A4 (6.64 ng/mL) was consistent with the reported values. The in vivo Ki of ketoconazole for renal P-gp was successfully estimated as 2.27 ng/mL, which was notably lower than reported in vitro 50% inhibitory concentration (IC₅₀) values ranged 223–2440 ng/mL due to different condition between in vitro and in vivo.     

Structure-Based Design of GNE-495, a Potent and Selective MAP4K4 Inhibitor with Efficacy in Retinal Angiogenesis

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Monitor: molecules and profiles

Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.     

Monitor: molecules and profiles

Monitor provides an insight into the latest developments in drug discovery through brief synopses of recent presentations and publications together with expert commentaries on the latest technologies. There are two sections: Molecules summarizes the chemistry and the pharmacological significance and biological relevance of new molecules reported in the literature and on the conference scene; Profiles offers commentary on promising lines of research, emerging molecular targets, novel technology, advances in synthetic and separation techniques and legislative issues.