Abstract
The distribution of highly lipophilic drugs into cerebrospinal fluid (CSF) is thought to be predictable from both assumptions of simple diffusion process and pH partition theory. We tried to predict CSF/plasma concentration ratio (CcsF/Cp) from the fraction of unbound drug in plasma (fp), pKa, and pH of blood and CSF and to compare the predicted CCSF/Cp values with the observed CCSF/Cp values collected from literatures.In the case of highly-lipophilic drugs, we found that the penetration into CSF could be predicted from various parameters we above. Since the penetration of more hydrophilic drugs into CSF could not be estimated from those parameters, we tried to predict CCSF/Cp values by using influx (PS1) rate constant from blood to brain and active efflux (kac) rate constant from brain to blood.The PS1 value was calculated from octanol/buffer partition coefficient (PC) and the diffusion constant across water (Dm) based on Sawada's report (Y.Sawada et al., Am.J.Physiol., 258, H1585 (1990)). The kac value was calculated on pharmacokinetic model considering the active efflux mechanisrr from brain to blood.A significant correlation (r=0.96) between kac and PC of each drug was observed.The predicted CCSF/Cp values based on this model wes comparable with the observed values.These findings suggested that the CCSF/Cp value of lipophilic or hydrophilic drugs was predictable from various biochemical, physicochemical and physiological parameters.
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