Cerebrospinal fluid uptake and peripheral distribution of centrally acting drugs: relation to lipid solubility.

In an anaesthetized dog model, serum kinetics and CSF entry were determined after i.v. administration of the following 8 drugs: salicylic acid (as acetylsalicylic acid), antipyrine, acetaminophen (paracetamol), lidocaine (lignocaine), trimipramine, amitriptyline, haloperidol, and imipramine. Kinetic variables were evaluated in relation to in-vitro lipophilicity, measured by the reverse-phase high-pressure liquid chromatographic (HPLC) retention index. After correction for individual values of serum binding (determined as the CSF: serum ratio at equilibrium), in-vivo volume of distribution was highly correlated with HPLC retention (r = 0.92). Conversely, the time of peak CSF concentration and the CSF entry half-life were negatively correlated with HPLC retention (r = -0.83 and -0.63, respectively). Thus lipophilicity is a physiochemical property which has an influence on the peripheral distribution of drugs as well as their rate of entry into CSF.