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 (CL(int,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,oct)) of 150 or above. The true octanol-water partition coefficients of the non-ionized drugs (P(oct)) were used to determine CL(int,h) and D for the unbound drugs (CL(int,h,f) and D(f), respectively), and CL(int,h,f) and D(f) for the non-ionized and unbound drugs (CL(int,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 CL(int,h,fu) (r = 0.974) than between log P(oct) and log CL(int,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 CL(int,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 CL(int,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.