Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract

Abstract 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.