The absorption mechanism of retinoic acids in the intestinal epithelium

Retinoids, are structural analogs of vitamin A and have cancer chemopreventive and chemotherapeutic activity. The preferred route of administration for cancer treatment is the oral route and it is therefore important to study their oral availability. A micellar system of sodium taurocholate and egg phosphatidylcholine (PC) in HEPES buffer was used to solubilize the retinoids due to their lipophilic nature and poor water solubility. The extent of solubilization of the retinoic acids in three types of micellar systems was studied. As the PC concentration in the micelle system was increased, the solubility of the retinoic acids also increased. It was also found that the degradation of the retinoids was greater in the micellar systems containing higher concentration of PC. Single pass in situ intestinal perfusion studies were performed to determine the effect of micellar system and the flow rate of perfusion on the permeability of N-ethyl retinamide (NER). It was found that the permeability was greater with the mixed micelles while the flow rate of perfusion had no significant effect on the permeability of NER.;The main focus of this work was to determine the uptake mechanism of retinoic acids in the intestinal epithelium and determine whether the intestinal membrane distinguished between the retinoic acids. The retinoic acids studied were all-trans retinoic acid (ATRA), 9-cis retinoic acid (9CRA) and 13-cis retinoic acid (13CRA) and the experimental setup used was the single pass in situ intestinal perfusion. The uptake of ATRA was found to follow a mixed mechanism of uptake with passive absorption predominating at high concentrations and a saturable process occurring at low concentrations. The uptake of 9CRA and 13CRA showed saturation indicating a carrier-mediated process. Further in vitro studies were performed with radiolabeled retinoic acids to determine if energy was required for the uptake process and if indeed the uptake of the retinoic acids was carrier-mediated. The in vitro studies showed that the uptake of 13CRA and ATRA was by passive diffusion while the uptake of 9CRA was a facilitated carrier-mediated process. ATRA inhibited 9CRA uptake indicating that it is a non-competitive inhibitor of 9CRA uptake.