Mechanism for Effective Lymphoid Cell and Tissue Loading Following Oral Administration of Nucleotide Prodrug GS-7340
Mechanism for Effective Lymphoid Cell and Tissue Loading Following Oral Administration of Nucleotide Prodrug GS-7340
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DOI：
10.1021/mp3002045
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发表时间：
2013-02-01
影响因子：
4.9
通讯作者：
Ray, Adrian S.
中科院分区：
文献类型：
--
作者：
Babusis, Darius;Phan, Truc K.;Ray, Adrian S.
GS-7340是替诺福韦(TFV)的前体药物，它比临床使用的TFV富马酸盐前药TFV更有效地将TFV输送到淋巴样细胞和组织中，从而在大大减少剂量的情况下产生更高的抗病毒效力，并降低全身TFV暴露。肠道和肝脏的首次提取对口服用于快速细胞内水解的前药构成了很大的障碍。为了了解GS-7340如何降低首过清除量成为一种有效的口服前药，对其体外渗透性和稳定性进行了研究，并对其在犬体内进行了详细的药代动力学研究。GS-7340在犬体内表现出浓度依赖的Caco-2细胞单层通透性和剂量依赖的口服生物利用度，从2 mg/kg的1.7%增加到20 mg/kg的24.7%，表明可饱和的肠道外排转运。考虑到门静脉插管犬肝脏抽出量的65%，高剂量GS-7340几乎完全吸收。与所提出的肠道外排转运的作用一致，低剂量GS-7340与转运抑制剂联合使用显著增加了GS-7340的暴露。有效的口服吸收和有效的淋巴样细胞负载的结果反映在狗口服后外周血单核细胞中药理活性代谢物TFV二磷酸的高水平和持续水平。总而言之，GS-7340通过使肠道外流转运体饱和而有效地进入体循环，通过其高溶解性以及通过在肠道和肝脏组织中保持足够的稳定性来促进目标细胞的负载。
GS-7340 is a prodrug of tenofovir (TFV) that more efficiently delivers TFV into lymphoid cells and tissues than the clinically used prodrug TFV disoproxil fumarate, resulting in higher antiviral potency at greatly reduced doses and lower systemic TFV exposure. First-pass extraction by the intestine and liver represents substantial barriers to the oral delivery of prodrugs designed for rapid intracellular hydrolysis. In order to understand how GS-7340 reduces first-pass clearance to be an effective oral prodrug its permeability and stability were characterized in vitro and detailed pharmacokinetic studies were completed in dogs. GS-7340 showed concentration-dependent permeability through monolayers of caco-2 cells and dose-dependent oral bioavallability in dogs, increasing from 1.7% at 2 mg/kg to 24.7% at 20 mg/kg, suggesting saturable intestinal efflux transport. Taking into account a 65% hepatic extraction measured in portal vein cannulated dogs, high dose GS-7340 is nearly completely absorbed. Consistent with the proposed role of intestinal efflux transport, coadministration of low dose GS-7340 with a transport inhibitor substantially increased GS-7340 exposure. The result of effective oral absorption and efficient lymphoid cell loading was reflected in the high and persistent levels of the pharmacologically active metabolite, TFV diphosphate, in peripheral blood mononuclear cells following oral administration to dogs. In conclusion, GS-7340 reaches the systemic circulation to effectively load target cells by saturating intestinal efflux transporters, facilitated by its high solubility, and by maintaining sufficient stability in intestinal and hepatic tissue.