Relationships between the Hepatic Intrinsic Clearance or Blood Cell-Plasma Partition Coefficient in the Rabbit and the Lipophilicity of Basic Drugs

Abstract

Abstract The relationships between drug lipophilicity and hepatic intrinsic clearance (CLint,h) or red blood cell-plasma partition coefficients (D) have been elucidated for ten highly lipophilic basic drugs with apparent octanol-water partition coefficients at pH 7.4 (Papp, oct) of 150 or above. The true octanol-water partition coefficients of the non-ionized drugs (Poct) were used to determine CLint,h and D for the unbound drugs (CLint,h,f and Df, respectively), and CLint,h,f and Df for the non-ionized and unbound drugs (CLint,h,fu and Dfu, respectively). The total clearance values were determined at steady state by infusion studies of individual drugs in rabbits. There was better correlation between log Poct, and log CLint,h,fu (r = 0.974) than between log Poct, and log CLint,h,f (r = 0.864). The D values were calculated from the blood-plasma concentration ratio. There was a better correlation between log Poct and log Dfu (r = 0.944) than between log Poct, and log Df (r = 0.612). The regression equations obtained were CLint,h,fu = 0.0875 × Poct1.338 and Dfu = 0.0108 × Poct0.970, respectively. These results show that the CLint,h and D of highly lipophilic basic drugs can be predicted from Poct by taking fu into consideration. By applying these parameters to a physiologically based pharmacokinetic model it might be possible to predict the pharmacokinetics of unknown basic drugs.