Investigation of utility of cerebrospinal fluid drug concentration as a surrogate for interstitial fluid concentration using microdialysis coupled with cisternal cerebrospinal fluid sampling in wild-type and Mdr1a(−/−) rats

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• 作者：Yoko Nagaya^a ; ^{y-nagaya@hhc.eisai.co.jp" class="auth_mail" title="E-mail the corresponding author} ; Yoshitane Nozaki^a ; Osamu Takenaka^b ; Ryuji Watari^a ; Kazutomi Kusano^a ; Tsutomu Yoshimura^a ; Hiroyuki Kusuhara^c
• 关键词：P-glycoprotein ; Central nervous system ; Brain ; Cerebrospinal fluid ; Interstitial fluid ; Microdialysis ; Rats ; Drug discovery
• 刊名：Drug Metabolism and Pharmacokinetics
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：31
• 期：1
• 页码：57-66
• 全文大小：1472 K

文摘

In drug discovery, the cerebrospinal fluid (CSF) drug concentration (C_CSF) has been used as a surrogate for the interstitial fluid (ISF) concentration (C_ISF). However, the C_CSF-to-C_ISF gradient suggested for P-glycoprotein (P-gp) substrates in rodents causes uncertainty in C_ISF estimations and subsequent pharmacokinetic-pharmacodynamic analyses. To evaluate the utility of C_CSF as a surrogate for C_ISF, this study directly compared the C_CSF with the C_ISF of 12 compounds, including P-gp substrates, under steady-state conditions in wild-type and Mdr1a(−/−) rats using microdialysis coupled with cisternal CSF sampling. In wild-type rats, the ISF-to-unbound plasma (K_p,uu,ISF) and CSF-to-unbound plasma (K_p,uu,CSF) concentration ratios of the P-gp substrates, except for metoclopramide, were lower than those of the non-P-gp substrates, and the K_p,uu,CSF values were within or close to 3-fold of the K_p,uu,ISF values for all the compounds examined. The K_p,uu,CSF values of the selected P-gp substrates increased in Mdr1a(−/−) rats with a similar magnitude to the K_p,uu,ISF values, resulting in the K_p,uu,CSF-to-K_p,uu,ISF ratios being unchanged. These results suggested that P-gp-mediated active efflux at the blood–brain barrier is a major determinant not only for C_ISF, but also for C_CSF, and that C_CSF can be used as a surrogate for C_ISF even for P-gp substrates in rats.