Lipophilicity and brain disposition of clonidine and structurally related imidazolidines.

The apparent partition coefficients (P') of clonidine and 27 of its structurally related imidazolidines were determined in the octanol/buffer (pH = 7.4) system as a measure of lipophilic behaviour. Lipophilicity of the imidazolidines is limited to the free bases and the principle of additivity is valid for this series of structurally similar compounds. Brain concentrations of clonidine and a number of its derivatives, achieved at the moment of maximal decrease in blood pressure, were determined following intravenous administration of anaesthetized rats. These brain concentrations represent the maximally attainable values. The ratio of log brain concentration/dose administered intravenously, log (Cbrain/Ci.v.), was employed as a measure of the penetration ability of the imidazolidines into the brain. The octanol/buffer (pH = 7.4) system proved a satisfactory reference model in order to describe the transport process of the present imidazolidines from the blood to the brain. The penetration ability of these compounds into the brain could be expressed mathematically by a highly significant, parabolic relationship in log P'. Ideal lipophilic character for optimal brain concentrations is connected with a log P' value of 2.16.