Dependency of cyclosporine tissue distribution and metabolism on the age and gender of rats after a single intravenous dose

In a previous study we demonstrated the dependency of cyclosporine (CyA) ph armacokinetics on the age and gender of Wistar rats given 10 mg/kg intraven ously. The present study has been conducted under the same experimental con ditions (10 mg/kg as a single intravenous dose) to identify the mechanisms behind such differences. On the one hand, drug distribution was studied by measuring the CyA levels in blood, liver, kidney, spleen, adipose tissue, s kin and muscle at 48 h post-treatment by using a specific fluorescence pola rization immunoassay (m-FPIA, Abbott Laboratories). Drug blood and tissue l evels in male rats were significantly higher than the female counterparts e xcept for adipose tissue where the concentrations were 2-fold higher in fem ales. In males, the highest CyA concentrations were observed in the liver, followed in rank order by kidney and spleen, fat, skin, muscle, then blood. On the contrary, females showed the highest drug levels in fat, followed b y liver, kidney, spleen, skin, muscle and blood. Age exerted a significant influence on CyA tissue levels in males but no effect was observed in femal es. The potential differences in drug metabolism were established by measur ing (HPLC) the amounts of CyA and its metabolites accumulated in faeces aft er hepatic biotransformation and biliary excretion. The amounts of circulat ing metabolites in blood as well as those accumulated and excreted in the l iver and urine were also estimated by using specific (In-FPIA) and non-spec ific fluorescence polarization immunoassay (p-FPIA, Abbott Laboratories), r espectively. The analysis of faeces revealed that AM9 was the major identif ied metabolite with females excreting lower amounts of unchanged CyA than m ales. In addition, the comparison of the AUC values corresponding to parent CyA and total CyA derivatives suggested that blood concentrations of CyA m etabolites were higher in females indicating higher biotransformation rates . Therefore, both CyA distribution and metabolism are responsible for the s ex-associated differences in drug pharmacokinetics previously found in rats . (C) 2000 Elsevier Science B.V. All rights reserved.