Localization of Cyclosporin a Absorption in Rat Small Bowel and the Effect of Bile

Abstract

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 (Cmax.), the time to reach Cmax. (tmax.), the absorption half-life (t1/2a), the elimination half-life (t1/2 lambda), and the mean residence time (MRT). 3. Cyclosporin A absorption in SI (AUC, 991 micrograms l-1 h) was nearly double that in more distal segments and decreased progressively (SII, 533 micrograms l-1 h; SIII, 470 micrograms l-1 h; SIV, 419 micrograms l-1 h). There were corresponding differences in Cmax.: 327 micrograms/l in SI and 201 micrograms/l, 169 micrograms/l and 151 micrograms/l in SII, SIII and SIV, respectively. Tmax. was shorter in SIV (0.9 h) than in other segments (1.3-1.5 h), but there were no significant differences between the segments for t1/2a, t1/2 lambda 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.(ABSTRACT TRUNCATED AT 250 WORDS)

Site-dependent contributions of P-glycoprotein and CYP3A to cyclosporin A absorption, and effect of dexamethasone in small intestine of mice

“…In contrast, CYP3A was expressed more strongly in the upper intestine than in the lower intestine in terms of both protein level and metabolic activity, and it was more strongly induced by dexamethasone in the lower intestine than in the upper intestine. These findings represent a significant extension of our previous study [21], and we confirmed that cyclosporin A was absorbed predominantly from the upper intestine in mice, as reported by Cakaloglu et al [35].…”

Contribution of Down-Regulation of Intestinal and Hepatic Cytochrome P450 3A to Increased Absorption of Cyclosporine A in a Rat Nephrosis Model

“…In the present study, examination of the absorption of CsA revealed that CsA was absorbed predominantly from the upper intestine, which was consistent with the findings of previous studies (Cakaloglu et al, 1993;Jin et al, 2006). Increased plasma concentrations of CsA in the nephrotic rats compared with the control rats indicates that the first-pass effects on CsA absorption by the intestine and liver decreased in the nephrosis model.…”

Variable effect of ursodeoxycholic acid on cyclosporin absorption after orthotopic liver transplantation

“…UDCA administration also induced no significant improvements in relative cyclosporin bioavailability in the five patients with Roux-en-Y enterostomy in this series. Such interventions reduce cyclosporin absorption because of the reduced length of bowel available for absorption [24], and recent experimental studies suggest that bile improves cyclosporin absorption in both the proximal and distal small intestine [3], so benefit with UDCA may have been expected. Chenodeoxycholate has been suggested to improve cyclosporin absorption by promoting micelle formation [4] and the weaker micelle-forming Rroperties of UDCA [19] may underlie its lesser potency.…”