Distribution to the brain and protein binding of 3' and 5-substituted 2',3'-dideoxyuridine derivatives, studied by microdialysis
Distribution to the brain and protein binding of 3' and 5-substituted 2',3'-dideoxyuridine derivatives, studied by microdialysis
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DOI：
10.1177/095632029700800105
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发表时间：
1997-01-01
影响因子：
--
通讯作者：
Stahle, L
中科院分区：
文献类型：
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作者：
Borg, N;Zhou, XX;Stahle, L
本研究的目的是研究一系列 3' 和 5-取代的 2',3'-二脱氧尿苷衍生物 (ddUD) 的血浆蛋白结合、半衰期和跨血脑屏障分布。微透析技术用于研究人血浆中的蛋白质结合（体外），并通过将微透析探针植入大脑纹状体和腓肠肌（体内）对大鼠的细胞外空间进行采样。通过带有 UV 检测的 HPLC 分析化合物。 ddUD 的辛醇/水分配系数在 0.08-0.84 之间变化。 ddUD 的蛋白质结合率约为 80%。 s.c.之后给药（25或50 mg·kg(-1)）时，脑和肌肉细胞外水平存在差异；脑内浓度为外周（肌肉）浓度的 0.18-0.36。包括齐多夫定、阿洛夫定和胸苷数据的多变量分析证明了尿苷类似物的物理化学特性和一些药代动力学特性之间的关系。分析表明，半衰期和蛋白质结合随着 pK(a) 的降低而增加。然而，对大脑的渗透与辛醇的分配无关。结论是，向大脑的转运主要并不依赖于亲脂屏障上的被动扩散，而是依赖于 ddUD 的其他化学特性。这暗示了特定的传输机制，例如胸苷载体。
The aim of this study was to investigate a series of 3' and 5-substituted 2',3'-dideoxyuridine derivatives (ddUD) with respect to plasma protein binding, half-life and distribution across the blood-brain barrier in the rat. The microdialysis technique was used to study protein binding in human plasma (in vitro), and to sample the extracellular space of rats with microdialysis probes implanted into the striatum of the brain and the gastrocnemic muscle (in vivo). The compounds were analysed by HPLC with UV-detection. The octanol/water partition coefficients of the ddUD varied from 0.08-0.84. The protein binding of the ddUDs was approximately 80%. After s.c. administration (25 or 50 mg kg(-1)), the brain and muscle extracellular levels differed; brain levels were 0.18-0.36 of peripheral (muscle) concentrations. A multivariate analysis, which included data on zidovudine, alovudine and thymidine, demonstrated a relationship between the physicochemical and some of the pharmacokinetic properties of uridine analogues. The analysis shows that half-life and protein binding increases with decreasing pK(a). However, penetration to the brain is not correlated with the partition into octanol. it is concluded that the transport to the brain is not primarily dependent upon passive diffusion over a lipophilic barrier but, rather, to other chemical properties of the ddUDs. This is suggestive of a specific transport mechanism, e.g. the thymidine carrier.