Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs
Polar molecular surface as a dominating determinant for oral absorption and brain penetration of drugs
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DOI：
10.1023/a:1015040217741
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发表时间：
1999-10-01
影响因子：
3.7
通讯作者：
Ploemen, JP
中科院分区：
文献类型：
--
作者：
Kelder, J;Grootenhuis, PDJ;Ploemen, JP
目的。研究口服吸收和大脑渗透作为极性分子表面积的函数。方法。研究了 45 种药物分子的脑部渗透测量数据。计算动态极性表面积并将其与脑穿透数据相关联。还计算了至少达到 II 期疗效研究的 776 种口服 CNS 药物的静态极性表面积。对一系列 1590 种口服非 CNS 药物进行了同样的研究，这些药物至少已达到 II 期疗效研究。结果。发现大脑穿透力和动态极表面积 (Angstrom(2)) 之间存在线性关系 (n = 45, R = 0.917, F-1,F-43 = 229)。大脑渗透力随着极性表面积的增加而降低。发现 776 个 CNS 药物和 1590 个非 CNS 药物的极性表面积分布存在明显差异。据推断，通过跨细胞途径被动转运的口服活性药物的极性表面积不应超过约120埃(2)。它们可以通过减少极性表面来适应大脑渗透
Purpose. To study oral absorption and brain penetration as a function of polar molecular surface area.Methods. Measured brain penetration data of 45 drug molecules were investigated. The dynamic polar surface areas were calculated and correlated with the brain penetration data. Also the static polar surface areas of 776 orally administered CNS drugs that have reached at least Phase II efficacy studies were calculated. The same was done for a series of 1590 orally administered non-CNS drugs that have reached at least Phase II efficacy studies.Results. A linear relationship between brain penetration and dynamic polar surface area (Angstrom(2)) was found (n = 45, R = 0.917, F-1,F-43 = 229). Brain penetration decreases with increasing polar surface area. A clear difference between the distribution of the polar surface area of the 776 CNS and 1590 non-CNS drugs was found. It was deduced that orally active drugs that are transported passively by the transcellular route should not exceed a polar surface area of about 120 Angstrom(2). They can be tailored to brain penetration by decreasing the polar surface to