Abstract

This study assesses the contribution of cyclosporin A (CsA) metabolism at sites of CsA-induced toxicity: kidney and liver, and a site of absorption, the intestine. With organ slice cultures (8 mm phi), it has been possible to demonstrate that the extrahepatic metabolism of CsA is significant. Both human kidney and colonic mucosal tissue metabolize CsA (1 microM, 24 hr) as analyzed by HPLC. The major metabolite M17 was formed in the kidney at an initial rate of 3 pmol/hr/mg slice protein, which was comparable to M17 formation in the liver slices (5 pmol/hr/mg slice protein). The rate of total CsA metabolism by human kidney slices represents about 42% the rate in liver slices. The metabolism of CsA to M17 was the same in the human kidney cell line 293; however, CsA metabolism was not detectable using human kidney microsomes, nor was metabolism clearly evident in either rat or dog kidney slice cultures. The metabolism of CsA by human colonic mucosal slices to at least three metabolites and the metabolism of CsA by the human intestinal cell line FHs74 Int indicates that the intestinal metabolism of CsA contributes to the first-pass effect of the drug. The liver proved to be the major site of CsA biotransformation in terms of the complexity of metabolites produced, whereas the human liver HepG2 cell line proved not to be a suitable model for CsA metabolism. A time course revealed that the first metabolites formed in the liver slice cultures were the monohydroxylated, M1 and M17, and N-demethylated, M21, followed by the secondary metabolites (including M8, M13, and M18).(ABSTRACT TRUNCATED AT 250 WORDS)