Relationships between the hepatic intrinsic clearance or blood cell-plasma partition coefficient in the rabbit and the lipophilicity of basic drugs

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 (P-app,P-oct) of 150 or above. The true octanol-water partition coefficients of the non-ionized drugs (P-oct) were used to determine CLint,h and D far the unbound drugs (CLint,h,f and D-f, respectively), and CLint,h,f and D-f for the non-ionized and unbound drugs (CLint,h,fu and D-fu, respectively). The total clearance values were determined at steady state by infusion studies of individual drugs in rabbits. There was better correlation between log P-oct and log CLint,h,fu (r=0.974) than between log P-oct 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 P-oct and log D-fu (r=0.944) than between log P-oct and log D-f (r = 0.612). The regression equations obtained were CLint,h,fu = 0.0875 x P-oct(1.338) and D-fu=0.0108 x P-oct(0.970), respectively. These results show that the CLint,h and D of highly lipophilic basic drugs can be predicted from P-oct by taking f(u) into consideration. By applying these parameters to a physiologically based pharmacokinetic model it might be possible to predict the pharmacokinetics of unknown basic drugs.