LOCALIZATION OF CYCLOSPORINE-A ABSORPTION IN RAT SMALL-BOWEL AND THE EFFECT OF BILE

1. Cyclosporin A absorption was examined after the instillation of approximately 2 mg/kg into four segments (mean length 15 cm) of rat small bowel, isolated in situ in fed Wistar female rats: SI (duodenum and proximal jejunum distal to the common bile duct); SII (distal jejunum); SIII (proximal ileum) and SIV (distal ileum). 2. Cyclosporin A concentrations in whole blood were assayed by an enzyme-mediated immunoassay for up to 4 h in samples drawn from the femoral vein and used to determine the following pharmacokinetic parameters: the area under the blood cyclosporin A concentration versus time curve (AUC, 0-4 h), the maximum blood concentration of cyclosporin A (C(max.)), the time to reach C(max.) (t(max.)), the absorption half-life (t1/2a), the elimination half-life (t1/2lambda), and the mean residence time (MRT). 3. Cyclosporin A absorption in SI (AUC, 991 mug l-1 h) was nearly double that in more distal segments and decreased progressively (SII, 533 mug l-1 h; SIII, 470 mug l-1 h; SIV, 419 mug l-1 h). There were corresponding differences in C(max.): 327 mug/l in SI and 201 mug/l, 169 mug/l and 151 mug/l in SII, SIII and SIV, respectively. T(max.) was shorter in SIV (0.9h) than in other segments (1.3-1.5 h), but there were no significant differences between the segments for t1/2a, t1/2lambda or MRT. 4. In the presence of continuous bile flow (diverted via a cannula for SIV), cyclosporin A absorption significantly increased by 23% in SI and by 50% in SIV, but the differential between absorption in SI and SIV was maintained. 5. We conclude that cyclosporin A is absorbed throughout the rat small intestine with the greatest absorption rate in the proximal duodenum and jejunum, and that bile significantly augments cyclosporin A absorption in both the proximal and particularly the distal small bowel.