It is essential to estimate concentrations of unbound drugs inside the hepatocytes to predict hepatic clearance, efficacy, and toxicity of the drugs. The present study was undertaken to compare predictability of the unbound hepatocyte-to-medium concentration ratios (K_p,uu) by two methods based on the steady-state cell-to-medium total concentration ratios at 37°C and on ice (K_p,uu,ss) and based on their initial uptake rates (K_p,uu,V0). Poorly metabolized statins were used as test drugs because of their concentrative uptake via organic anion-transporting polypeptides. K_p,uu,ss values of these statins provided less interexperimental variation than the K_p,uu,V0 values, because only data at longer time are required for K_p,uu,ss K_p,uu,V0 values for pitavastatin, rosuvastatin, and pravastatin were 1.2- to 5.1-fold K_p,uu,ss in rat hepatocytes; K_p,uu,V0 values in human hepatocytes also tended to be larger than corresponding K_p,uu,ss To explain these discrepancies, theoretical values of K_p,uu,ss and K_p,uu,V0 were compared with true K_p,uu (K_p,uu,true), considering the inside-negative membrane potential and ionization of the drugs in hepatocytes and medium. Membrane potentials were approximately -30 mV in human hepatocytes at 37°C and almost abolished on ice. Theoretical equations considering the membrane potentials indicate that K_p,uu,ss values for the statins are 0.85- to 1.2-fold K_p,uu,true, whereas K_p,uu,V0 values are 2.2- to 3.1-fold K_p,uu,true, depending on the ratio of the passive permeability of the ionized to nonionized forms. In conclusion, K_p,uu,ss values of anions are similar to K_p,uu,true when the inside-negative membrane potential is considered. This suggests that K_p,uu,ss is preferable for estimating the concentration of unbound drugs inside the hepatocytes.

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