The comparison between in-vivo and in-vitro tissue-to-plasma concentration ratio of drug unbound (Kp,f) has been made using quinidine as a model for weak basic drugs. In-vitro Kp,f-values were calculated from the binding data to tissue homogenates determined by equilibrium dialysis. In-vivo Kp,f-values were calculated from the tissue distribution data after intravenous administration of quinidine, by considering the difference in the unbound concentration between plasma and the tissues produced by the pH difference across the cell membrane. It was concluded that the extensive tissue distribution of quinidine observed in-vivo may be explained by tissue binding and the pH-difference across the cell membrane in most tissues.