0090-9556/97/2508-0917-0920$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 8

Pulmonary Delivery of Intratracheally Instilled and Aerosolized Cyclosporine A to Young and Adult Rats

Witold Taljanski, Stefan G. Pierzynowski, Pal D. P. Lundin, Björn R. Weström, Stefan Eirefelt, Jerzy Podlesny, Magnus Dahlbäck, Henryka Siwinska-Golebiowska, and Börje W. Karlsson

Department of Immunology, National Research Institute of Mother and Child (W.T., H.S.-G.); Department of Animal Physiology, University of Lund (S.G.P., P.D.P.L., B.R.W., B.W.K.); Preclinical R & D, Department of Pharmacology, Astra Draco (S.E., M.D.); Department of Pharmacology, The Children's Memorial Health Institute (J.P.)

The delivery and pharmacokinetics of cyclosporine A (CyA) given locally to the airways or iv was evaluated in young and adult rats. After intratracheal (i.t.) instillation of saline suspended CyA to adult rats, the CyA plasma levels peaked at 30 min with a bioavailability of 78.1 ± 6.9%. After the i.t. instillation of CyA with micelles forming surfactant, Cremophor EL, in adult and young rats, the plasma levels peaked at 5 min with a bioavailability of 77.5 ± 7.2% and 66.3 ± 4.5%, respectively. The bioavailability of aerosolized CyA was 80.1 ± 4.1% in adults. Thus, CyA is absorbed by the lungs into the systemic circulation of the rat in high amounts, independent of age and type of delivery system. Long-term treatment with i.t. instillations did not affect body weight gain in young and adult rats, and no histopathological changes were found in the lungs. It is important to emphasize that CyA plasma clearance in young rats was lower and elimination half-life longer than in adults. The slow elimination of CyA in young rats indicated profound pharmacokinetic age differences for this species.