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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 …