Hepatobiliary disposition of rhodamine 123 in isolated perfused rat livers

Abstract

The disposition of rhodamine 123 (RH-123), a known marker of P-glycoprotein, and its liver-generated glucuronide metabolite (RH-Glu), a marker of Mrp2, was studied in an isolated perfused rat liver model. Livers were perfused with a buffer containing 0.1 µg ml⁻¹ RH-123 for 30 or 60 min or for 30 min followed by 90 min of drug-free perfusion, and the concentrations of the drug and its metabolites were determined in the perfusate, bile, and the liver tissue. The outlet perfusate concentrations of RH-123 and RH-Glu reached an apparent plateau during the continuous infusion of the drug, with a very extensive extraction ratio of approximately 96% for the parent drug. However, the biliary excretion rates of both RH-123 and generated RH-Glu continued to rise almost linearly during the entire 60 min of drug infusion. This was associated with a linear increase in the amount of RH-123 recovered in the liver between 30 and 60 min of drug infusion, resulting in a significant (>50% of the administered dose) recovery of the marker in the liver both after 30 and 60 min of perfusion. Additionally, the washout experiments showed that the declines in the biliary excretion rates of RH-123 and RH-Glu were parallel to that of RH-123 concentration in the liver in the absence of drug input. The hepatobiliary disposition of RH-123 in rats is unique because of its substantial and time-dependent accumulation in the liver, resulting in a lack of steady-state in its biliary excretion despite apparent steady-state in the perfusate.

Keywords::

• Pharmacokinetics
• isolated perfused rat liver
• hepatobiliary disposition
• P-glycoprotein
• multidrug resistance protein 2