模拟肠道转运蛋白和酶活性为替诺福韦Disoproxil延胡索酸酯为基础的生理药代动力学模型。
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苔藓DM, Domanico P,沃特金斯M,公园,兰多夫R,写作年代,Rajoli RKR,霍布森J, Rannard年代,Siccardi M,欧文
模拟肠道转运蛋白和酶活性为替诺福韦Disoproxil延胡索酸酯为基础的生理药代动力学模型。
Antimicrob代理Chemother。2017年6月27日,61 (7)。pii: AAC.00105-17。doi: 10.1128 / AAC.00105-17。打印2017年7月。
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28416547 (在PubMed]
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替诺福韦disoproxil延胡索酸酯(TDF),泰诺福韦的前体药物,口服生物利用度(25%)受到肠道运输(22)和肠道退化(羧酸酯酶)。然而,细胞腔的胰酶的影响并不完全了解。基于生理药代动力学(PBPK)建模工具从体外数据估计药物暴露。本研究旨在开发一个PBPK模型,包括腔的酶活性通知剂量减少策略。TDF和替诺福韦稳定评估猪胰脂肪酶浓度(0、0.48、4.8、48和480 U /毫升的脂肪酶;TDF约1毫米;37摄氏度;0到30分钟)。使用质谱样品进行了分析。TDF稳定和渗透数据允许计算吸收率在人类PBPK模型来预测每日一次的等离子体照射后6天剂量300毫克的TDF。 Regional absorption of drug was simulated across gut segments. TDF was degraded by pancrelipase (half-lives of 0.07 and 0.62 h using 480 and 48 U/ml, respectively). Previously reported maximum concentration (Cmax; 335 ng/ml), time to Cmax (Tmax; 2.4 h), area under the concentration-time curve from 0 to 24 h (AUC0-24; 3,045 ng . h/ml), and concentration at 24 h (C24; 48.3 ng/ml) were all within a 0.5-fold difference from the simulated Cmax (238 ng/ml), Tmax (3 h), AUC0-24 (3,036 ng . h/ml), and C24 (42.7 ng/ml). Simulated TDF absorption was higher in duodenum and jejunum than in ileum (p<0.05). These data support that TDF absorption is limited by the action of intestinal lipases. Our results suggest that bioavailability may be improved by protection of drug from intestinal transporters and enzymes, for example, by coadministration of enzyme-inhibiting agents or nanoformulation strategies.