Pharmacokinetic evaluation of the blood-to-lymph transfer of cyclosporin A in rats.

The blood-to-lymph transfer kinetics of cyclosporin A (CyA) were investigated in thoracic duct cannulated rats after a 3 mg kg-1 i.v. bolus injection of tritium-labelled drug. Blood CyA concentrations declined bi-exponentially with a terminal half-life of 13.1 +/- 1.8 h. The appearance rate of CyA in the lymph was also bi-phasic, initially rising and then declining in parallel with the concentrations of CyA in the blood. A pharmacokinetic model describing the blood-to-lymph transfer kinetics of CyA is presented. From the slopes of graphs relating the appearance rate of CyA in the lymph to the corresponding midpoint blood drug concentration, the estimated blood-to-lymph clearance rate of CyA (ClL)b was 0.262 +/- 0.132 ml h-1. (ClL)b was positively correlated with the average lymph flow rate (QL) but was significantly less than QL. On the other hand, the plasma-to-lymph clearance rate of CyA (ClL)p of 0.393 +/- 0.198 ml h-1 was positively correlated and similar to QL. Lymph concentrations of CyA were approximately 40-60 per cent of the corresponding blood concentrations. The results of this investigation showed the existence of an intervening compartment between the blood and lymph fluids which would be consistent with the presence of lymph nodes. It was shown that the blood-to-lymph transfer of CyA was dependent on the flow rate of the lymph and that CyA appeared to be cleared from the plasma (or serum) fraction of the blood.