Abstract

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 andK _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 · min⁻¹ · g⁻¹ of liver): 10.08–67.41; CL_pT (ml · min⁻¹ · g⁻¹of liver): 10.80–5.35; PS (ml · min⁻¹ · 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.