Contribution of lysosomes to concentrative uptake of DX-9065a into rat liver

This study evaluates the distribution profile in tissues and concentrative uptake mechanism for a cationic compound of DX-9065a in rats. After a single intravenous dosing of [14C]-DX-9065a to male rats, higher levels of radioactivity were observed in kidney and liver. Moreover, the radioactivity in the liver continuously increased up to 6 h after intravenous dosing and a concentrative uptake of the drug against the radioactivity gradient between plasma and liver, showing Kp value of 90.7. In contrast, carrier-mediated systems did not play a significant role in the uptake of DX-9065a by hepatocytes. A subcellular distribution study was conducted by means of Percoll density gradient centrifugation and revealed a high affinity of the compound with the lysosomes. It was concluded that DX-9065a permeated into hepatocyte across the membrane primarily by passive diffusion, and the consequent process of lysosomal trapping played a major role in the concentrative uptake of the drug into the liver.