Alterations in intestinal carrier mediated transport following thermal injury in rats and the potential role of luminal cytokines

Introduction: Although the integrity of the intestinal barrier is diminished following thermal injury, alterations in specific drug transport mechanisms have been poorly elucidated. Effective intestinal permeability (Peff) is one rate-limiting factor in drug transport across the intestine. Carrier mediated drag transport via the di and tripeptide transporter (PepT1) was assessed by single pass perfusions of the rat jejunum using cepbalexin as a marker substrate. Methods: Using a parallel design, male Sprague Dawley rats (270-470 g) assigned to burn (n=15) or control (n=15) groups, were anesthetized, underwent laparotomy and had the proximal jejunum cannulated. Subsequently, the segment was perfused with isotonic buffer containing cephalexin (0.5 mM) for 120 minutes. The burn group underwent a 30% TBSA full thickness scald bum 24 hours prior to the intestinal perfusion. Intestinal perfusate samples were assayed for IL-6, IL-10, and TNF-α at 10, 40, 80, and 120 minutes using ELISA. Cephalexin concentrations were determined by HPLC. Cephalexin (Peff) was calculated using the Plug Flow Model. Level of significance was set at p<0.05. Results: The Peff of cephalexin was significantly greater in the burn group as compared to controls (5.24 ± 1.63×10^-5 vs 3.47 ± 2.39×10^-5 cm/sec). All 3 cytokines were detected in the intestinal perfusate from both groups. Burned rats bad significantly lower IL-6 concentrations at 80 and 120 minutes (11.5 ± 12.7 vs 32.0 ± 16.9 and 13.7 ± 14.1 vs 32.9 ± 14.0 pg/ml) and higher IL-10 concentrations at 40 and 120 minutes (10.5 ± 11.5 vs 0.937 ± 2.03 and 8.72 ± 6.52 vs 0.906 ± 3.43 pg/ml). The 10 minute TNF-α concentrations were significantly higher (40.1 ± 25.8 vs 221 ± 32.0) in the burn group. Significant positive correlations between cephalexin transport (Peff) and the 80 minute IL-6 and 120 minute TNF-α were detected in the burn group. There was no significant difference in water flux. Conclusions: Cephalexin intestinal transport is significantly increased 24 hours following thermal injury in rats and this may be due to upregulation of PepT1 and/or increased paracellular transport The decreased response of the intestinal immune system, as evidenced by decreased luminal IL-6 and increased IL-10 concentrations, may play a role in intestinal barrier function in thermal injury and thus drug transport.