Overton's Rule Helps To Estimate the Penetration of Anti-Infectives into Patients' Cerebrospinal Fluid
Overton's Rule Helps To Estimate the Penetration of Anti-Infectives into Patients' Cerebrospinal Fluid
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DOI：
10.1128/aac.00437-11
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发表时间：
2012-02-01
影响因子：
4.9
通讯作者：
Nau, Roland
中科院分区：
文献类型：
--
作者：
Djukic, Marija;Munz, Martin;Nau, Roland
1900年，恩斯特·奥弗顿（Ernst Overton）发现，苯胺类染料能否通过活细胞的细胞膜，取决于染料的亲脂性。大脑被由脂质层组成的屏障所包围，脂质层拥有几个向内和向外的主动运输系统。在无脑膜炎症的情况下，由脑脊液浓度-时间曲线下面积（AUC） （AUC(CSF)）与血清(AUC（CSF)/AUC(S)）之比估计的抗感染药物在人脑脊液（CSF）中的渗透能力与pH 7.0时脂水分配系数（log D）呈正相关(Spearman等级相关系数r(S) = 0.40；P = 0.01)，与分子质量（MM）呈负相关(r(S) = 0.33；P = 0.04)。血清中未结合部分AUC(AUC（CSF)/游离部分AUC(S,free)）与log D呈强相关(r(S) = 0.67；P < 0.0001)。存在脑膜炎症时，AUC(CSF)/AUC(S)也与log D呈正相关(r(S) = 0.46；P = 0.002)，与MM呈负相关(r(S) = 0.37；P = 0.01)。AUC(CSF)/AUC（S,free）与log D的相关性(r(S) = 0.66；P < 0.0001)与没有脑膜炎症时一样强。尽管存在这些明显的相关性，但奥弗顿规则只能解释个别化合物在脑脊液渗透方面的部分差异。脑脊液退出部位（腰椎与脑脊液）、患者年龄、潜在疾病、主动转运以及药物对药代动力学的改变似乎也强烈影响所研究药物的脑脊液渗透。
In 1900, Ernst Overton found that the entry of anilin dyes through the cell membranes of living cells depended on the lipophilicity of the dyes. The brain is surrounded by barriers consisting of lipid layers that possess several inward and outward active transport systems. In the absence of meningeal inflammation, the cerebrospinal fluid (CSF) penetration of anti-infectives in humans estimated by the ratio of the area under the concentration-time curve (AUC) in CSF (AUC(CSF)) to that in serum (AUC(CSF)/AUC(S)) correlated positively with the lipid-water partition coefficient at pH 7.0 (log D) (Spearman's rank correlation coefficient r(S) = 0.40; P = 0.01) and negatively with the molecular mass (MM) (r(S) = 0.33; P = 0.04). The ratio of AUC(CSF) to the AUC of the fraction in serum that was not bound (AUC(CSF)/AUC(S,free)) strongly correlated with log D (r(S) = 0.67; P < 0.0001). In the presence of meningeal inflammation, AUC(CSF)/AUC(S) also correlated positively with log D (r(S) = 0.46; P = 0.002) and negatively with the MM (r(S) = 0.37; P = 0.01). The correlation of AUC(CSF)/AUC(S,free) with log D (r(S) = 0.66; P < 0.0001) was as strong as in the absence of meningeal inflammation. Despite these clear correlations, Overton's rule was able to explain only part of the differences in CSF penetration of the individual compounds. The site of CSF withdrawal (lumbar versus ventricular CSF), age of the patients, underlying diseases, active transport, and alterations in the pharmacokinetics by comedications also appeared to strongly influence the CSF penetration of the drugs studied.