Structure-hepatic disposition relationships for cationic drugs in isolated perfused rat livers: transmembrane exchange and cytoplasmic binding process.

This work studied the structure-hepatic disposition relationships for cationic drugs of varying lipophilicity using a single-pass, in situ rat liver preparation. The lipophilicity among the cationic drugs studied in this work is in the following order: diltiazem > propranolol > labetalol > prazosin > antipyrine > atenolol. Parameters characterizing the hepatic distribution and elimination kinetics of the drugs were estimated using the multiple indicator dilution method. The kinetic model used to describe drug transport (the "two-phase stochastic model") integrated cytoplasmic binding kinetics and belongs to the class of barrier-limited and space-distributed liver models. Hepatic extraction ratio (E) (0.30--0.92) increased with lipophilicity. The intracellular binding rate constant (k(on)) and the equilibrium amount ratios characterizing the slowly and rapidly equilibrating binding sites (K(S) and K(R)) increase with the lipophilicity of drug (k(on): 0.05--0.35 s(-1); K(S): 0.61--16.67; K(R): 0.36--0.95), whereas the intracellular unbinding rate constant (k(off)) decreases with the lipophilicity of drug (0.081--0.021 s(-1)). The partition ratio of influx (k(in)) and efflux rate constant (k(out)), k(in)/k(out), increases with increasing pK(a) value of the drug [from 1.72 for antipyrine (pK(a) = 1.45) to 9.76 for propranolol (pK(a) = 9.45)], the differences in k(in/kout) for the different drugs mainly arising from ion trapping in the mitochondria and lysosomes. The value of intrinsic elimination clearance (CL(int)), permeation clearance (CL(pT)), and permeability-surface area product (PS) all increase with the lipophilicity of drug [CL(int) (ml x min(-1) x g(-1) of liver): 10.08--67.41; CL(pT) (ml x min(-1) x g(-1) of liver): 10.80--5.35; PS (ml x min(-1) x g(-1) of liver): 14.59--90.54]. It is concluded that cationic drug kinetics in the liver can be modeled using models that integrate the presence of cytoplasmic binding, a hepatocyte barrier, and a vascular transit density function.