0090-9556/97/2507-0873-0880$02.00/0
DRUG METABOLISM AND DISPOSITION
Copyright © 1997 by The American Society for Pharmacology and Experimental Therapeutics
Vol. 25, No. 7

Human and Rat Lung Biotransformation of Cyclosporin A and Its Derivatives Using Slices and Bronchial Epithelial Cells

Alison E. M. Vickers, Rosa M. Jimenez, M. Carina Spaans, Veronique Pflimlin, Robyn L. Fisher, and Klaus Brendel

Preclinical Safety, Novartis Pharma Ltd. (A.E.M.V., M.C.S., R.M.J., V.P.); and Department of Pharmacology and Toxicology, University of Arizona (R.L.F., K.B.)

Lung biotransformation of the immunosuppressants, cyclosporin A (CSA), the hydroxyethyl derivative SDZ IMM 125 (IMM), and the methylcarbonate derivative SDZ SCP 764 (SCP), was demonstrated in slices from human and rat. The major biotransformation pathway for CSA and IMM (0.1-10 µM) was hydroxylation at amino acid 1 to form AM1 or IMM1, while for SCP it was an esterase cleavage of the methylcarbonate group to form AM1 in both species. The initial rate (0-1 hr) of human total metabolite formation increased proportionally with substrate concentration. AM1 formation was five times greater from SCP, an esterase pathway, than CSA, an oxidative pathway which was inhibited (50%) by ketoconazole. At 24 hr human lung CSA metabolite formation was greater than IMM (3-fold) or SCP (2-fold), whereas rat lung and liver and human bronchial epithelial cell SCP metabolite formation generally exceeded CSA or IMM metabolism.

CSA biotransformation is expected to occur throughout the human lung as demonstrated by the similar metabolite profile and extent of metabolism by slices derived from five different regions. The scaling of slice total metabolism to organ metabolism revealed that initially lung CSA metabolite formation would be equal to liver but with time liver metabolism would exceed lung for human and rat.

This study has demonstrated that human and rat lung are metabolically active, exhibiting oxidative and esterase pathways toward cyclosporin derivatives. The lung will play an important role in this metabolism, particularly when administered via inhalation; however, the liver will also be a major organ involved in the total clearance of these compounds.