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 t heir impact on the oral absorption of a model peptide drug, salmon calciton in (sCT), in conscious beagle dogs. Methods. Male beagle dogs were surgically prepared with subdermal Intestina l 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, respec tively. Three treatments were performed: (1) a radiopaque dye and citric ac id (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 prot ease trypsin, the rate of degradation of sCT in the GI lumen is dependent u pon the regional pH, activity of digestive enzymes and the concentration of sCT at the site of absorption. Fluoroscopy results clearly skewed that whe n the radiopaque dye was infused into the duodenum and capsule disintegrati on occurred early, there was significant dilution and spreading of the exci pients throughout a large section of the upper small intestine (USI). Howev er, when the radiopaque dye was infused into the ileum and capsule disinteg ration occurred in the lower small intestine (LSI), the excipients moved al ong 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. Ln the LSI, diluti on 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 disinte gration occurred in the LSI. Conclusions. Since significantly less dilution and spreading occurred in th e LSI, the exposure of the intestine to pharmaceutical excipients and sCT w as more concentrated resulting in a higher fraction of sCT absorbed. The re sults of this study demonstrate that intestinal mixing kinetics have a dram atic impact on the ability of pharmaceutical excipients to modulate the ora l bioavailability of peptide drugs like sCT.