Regional differences in intestinal spreading and pH recovery and the impact on salmon calcitonin absorption in dogs.

PURPOSE: To investigate the regional influence of intestinal spreading and pH recovery on the performance of drug and excipient delivery systems and their impact on the oral absorption of a model peptide drug, salmon calcitonin (sCT), in conscious beagle dogs.
METHODS: Male beagle dogs were surgically prepared with subdermal Intestinal Access Ports (IAP). The catheter from one port was placed in the duodenum and the other in the ileum. Fluoroscopy and Heidelberg pH capsule studies were performed to characterize intestinal spreading and pH recovery, respectively. Three treatments were performed: (1) a radiopaque dye and citric acid (CA) were infused into the intestinal segments, (2) a radiopaque powder capsule containing CA was given orally, and (3) capsules containing CA and sCT were given orally. Regular blood samples were collected and analyzed by radioimmunoassay (RIA) to determine the absorption characteristics of sCT.
RESULTS: Since sCT is an excellent substrate for the pancreatic serine protease trypsin, the rate of degradation of sCT in the GI lumen is dependent upon the regional pH, activity of digestive enzymes and the concentration of sCT at the site of absorption. Fluoroscopy results clearly showed that when the radiopaque dye was infused into the duodenum and capsule disintegration occurred early, there was significant dilution and spreading of the excipients throughout a large section of the upper small intestine (USI). However, when the radiopaque dye was infused into the ileum and capsule disintegration occurred in the lower small intestine (LSI), the excipients moved along as a bolus (i.e., plug). The pH monitoring results were consistent with the fluoroscopy results. The pH dropped only momentarily and rose quickly in the USI consistent with well-stirred mixing kinetics. In the LSI, dilution and spreading were minimal and the drop in pH was greater and persisted for a longer period of time. Plasma levels of sCT were maximal when disintegration occurred in the LSI.
CONCLUSIONS: Since significantly less dilution and spreading occurred in the LSI, the exposure of the intestine to pharmaceutical excipients and sCT was more concentrated resulting in a higher fraction of sCT absorbed. The results of this study demonstrate that intestinal mixing kinetics have a dramatic impact on the ability of pharmaceutical excipients to modulate the oral bioavailability of peptide drugs like sCT.