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.
Ochs
H R
HR
Greenblatt
D J
DJ
Abernethy
D R
DR
Arendt
R M
RM
Gerloff
J
J
Eichelkraut
W
W
Hahn
N
N
D000818:Animals; D004285:Dogs; D006207:Half-Life; D007700:Kinetics; D008055:Lipids; D004364:Pharmaceutical Preparations / Q000134:cerebrospinal fluid* / Q000378:metabolism; D012995:Solubility
D008055:Lipids; D004364:Pharmaceutical Preparations