PHARMACOKINETICS AND ABSOLUTE BIOAVAILABILITY OF CYCLOSPORINE FOLLOWING INTRAVENOUS AND ABOMASAL ADMINISTRATION TO SHEEP

Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0.45 +/- 0.05 L h-1 kg-1), distribution volume (4.4 +/- 2.0 L kg-1), mean residence time (9.6 +/- 4.1 h) and half-life (12.1 +/- 3.1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26.3 mg kg-1. but was curvilinear above this dose. Abomasal bioavailability at 6.4 mg kg-1 was 0.26 +/- 0.09, and mean absorption time was 4.7 +/- 11.1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.