Hepatic disposition of cyclosporine A in isolated perfused rat livers.

PURPOSE To develop an isolated perfused rat liver model to study the hepatic disposition of cyclosporine A (CyA) in both sexes. METHODS Livers were isolated from male (n = 6) and female (n = 7) rats and perfused with a physiological buffer in a single-pass manner. A bolus 1-mg dose of CyA was injected into the inlet catheter and periodical samples (0-15 min) were collected from the outlet perfusate. The concentrations of CyA in the outlet perfusate, collected bile (0-15 min), and liver tissue (at the end of perfusion) were quantitated by HPLC and subjected to statistical moment analysis. RESULTS The dilution curves of CyA in the outlet perfusate exhibited unusually long terminal phases due to large volume of distribution of the drug (approximately 100 mL/g) and its slow release from binding sites in the liver (net release rate constant of approximately 0.020 min(-1)). This was in contrast to the rapid uptake of the drug, indicated by significant amounts of the intact drug (>40%) taken up during one single pass through the liver. Consequently, the liver tissue:perfusate distribution ratio of CyA was very high (approximately 220). No significant differences were found between the male and female livers in any of the estimated parameters. CONCLUSIONS The tissue binding of cyclosporine A is substantial, slowly reversible, and gender-independent in isolated perfused rat livers.