Analysis of blood-brain barrier permeability of drugs using forensically obtained human cerebrospinal fluid and plasma in Japan.

Distribution coefficient the cerebrospinal fluid (CSF) concentration ratios of unbound drugs to serum (Ks,uu,CSF) were calculated from drugs detected in serum and CSF obtained at forensic autopsies in Japan, and documented values of serum protein binding rates of the drugs. Of the 39 compounds detected in 51 specimens, 21 drugs with a case number of 2 or more were included in the analysis. The calculated liposolubility parameter (cLogP) of each drug was corrected for the square root of the molecular weight to calculate the Log [Pc × MW-1/2] value. A tendency for drugs with higher liposolubility to have higher permeability into the cerebral spinal fluid was observed. The Ks,uu,CSF values were particularly high for diphenhydramine and haloperidol, which are substrates for transporters in the uptake system. When the correlation between Ks,uu,CSF and Log [Pc × MW-1/2] was examined after excluding diphenhydramine and haloperidol, a significant positive correlation (R = 0.465, p < 0.05) was found. It is planned to publish a database of these individual values and update it whenever new drug data becomes available to make these data widely available to other researchers.