Effect of tissue degeneration on drug transfer across in vitro rat intestine.

A modified rat intestinal sac technique involving a closed circulation of the mucosal drug solution through the lumen was developed with the aim of clarifying the influence of tissue degeneration on drug transfer in the current in vitro methods for studying intestinal absorption. Data on salicylate transfer in agreement with the literature reports on the everted rat intestinal sac technique were obtained with the physiological Tyrode or Krebs-Henseleit buffers. In neither case was the transfer rate influenced by a progressive disruption of the mucosa which resulted upon histological examination of the perfused sacs. The rate-controlling barrier to drug transport, probably located in the inner tissues, maintained a constant permeability to salicylate in the said physiological solutions over a period of 80 min. On the other hand, the gut permeability underwent a nonreversible alteration by each of two phosphate buffers employed in the past for studies with the everted rat intestine. The liability of such an alteration to occur at nonphysiological pH was found to be a major obstacle to the study of the effects of pH on drug transport. A case where the reversibility of these effects could be verified allowed us to state that unionized salicylic acid was transported at a 8.6-fold faster rate than salicylate. Apart from the inherent limitations of the in vitro preparation, the technique presented here provides the following advantages over the classical everted intestinal sac technique: 1) eversion of intestine is avoided; 2) constancy of the mucosal drug concentration is guaranteed throughout the experiment; 3) volume variations of the serosal solution due to water absorption by the intestinal tissues and/or to osmotic phenomena are negligible.