Brandl Michael, Wu Xiaoyang, Holper Marites, Hong Lei, Jia Zhongjiang, Birudaraj Raj, Reddy Micaela, Alfredson Tom, Tran Tony, Larrabee Susan, Hadig Xu, Sarma Keshab, Washington Carla, Hill George, Smith David B
Roche Palo Alto, LLC, 3431 Hillview Avenue, Palo Alto, CA 94304, USA.
Drug Dev Ind Pharm. 2008 Jul;34(7):683-91. doi: 10.1080/03639040701836636.
The nucleoside analog R1479 is a potent and highly selective inhibitor of NS5b-directed hepatitis C virus (HCV) RNA polymerase in vitro. Because of its limited permeability, lipophilic prodrugs of R1479 were screened. Selection of the prodrug involved optimization of solubility, permeability, and stability parameters. R1626 has dissociation constant, intrinsic solubility, log partition coefficient (n-octanol water), and Caco-2 permeability of 3.62, 0.19 mg/mL, 2.45, and 14.95 x 10(-6) cm/s, respectively. The hydrolysis of the prodrug is significantly faster in the Caco-2 experiments than in hydrolytic experiments, suggesting that the hydrolysis is catalyzed by enzymes in the cellular membrane. Using GastroPlus, the physical properties of R1626 successfully predict the dose dependence of the pharmacokinetics in humans previously studied. The program predicts that if the particle size of R1626 is less than 25 microm, it will be well absorbed. Prodrugs with a solubility of greater than 100 microg/mL and permeability in the Caco-2 assay greater than 3 x 10(-6) cm/s are expected to achieve a high fraction absorbed.
核苷类似物R1479在体外是一种有效的、高度选择性的NS5b导向的丙型肝炎病毒（HCV）RNA聚合酶抑制剂。由于其渗透性有限，对R1479的亲脂性前药进行了筛选。前药的选择涉及溶解度、渗透性和稳定性参数的优化。R1626的解离常数、固有溶解度、对数分配系数（正辛醇/水）和Caco-2渗透性分别为3.62、0.19 mg/mL、2.45和14.95×10⁻⁶ cm/s。在前药的Caco-2实验中，其水解速度明显快于水解实验，这表明水解是由细胞膜中的酶催化的。使用GastroPlus软件，R1626的物理性质成功预测了先前研究中人体药代动力学的剂量依赖性。该程序预测，如果R1626的粒径小于25微米，它将被很好地吸收。预计溶解度大于100微克/毫升且在Caco-2试验中渗透性大于3×10⁻⁶ cm/s的前药将实现高吸收分数。
