Abstract
Purpose. To investigate the regional influence of intestinal spreadingand pH recovery on the performance of drug and excipient deliverysystems and their impact on the oral absorption of a model peptidedrug, salmon calcitonin (sCT), in conscious beagle dogs.
Methods. Male beagle dogs were surgically prepared with subdermalIntestinal Access Ports (IAP). The catheter from one port was placedin the duodenum and the other in the ileum. Fluoroscopy and HeidelbergpH capsule studies were performed to characterize intestinal spreadingand pH recovery, respectively. Three treatments were performed: (1)a radiopaque dye and citric acid (CA) were infused into the intestinalsegments, (2) a radiopaque powder capsule containing CA was givenorally, and (3) capsules containing CA and sCT were given orally.Regular blood samples were collected and analyzed byradioimmunoassay (RIA) to determine the absorption characteristics of sCT.
Results. Since sCT is an excellent substrate for the pancreatic serineprotease trypsin, the rate of degradation of sCT in the GI lumen isdependent upon the regional pH, activity of digestive enzymes and theconcentration of sCT at the site of absorption. Fluoroscopy resultsclearly showed that when the radiopaque dye was infused into theduodenum and capsule disintegration occurred early, there wassignificant dilution and spreading of the excipients throughout a large sectionof the upper small intestine (USI). However, when the radiopaque dyewas infused into the ileum and capsule disintegration occurred in thelower small intestine (LSI), the excipients moved along as a bolus (i.e.,plug). The pH monitoring results were consistent with the fluoroscopyresults. The pH dropped only momentarily and rose quickly in the USIconsistent with well-stirred mixing kinetics. In the LSI, dilution andspreading were minimal and the drop in pH was greater and persistedfor a longer period of time. Plasma levels of sCT were maximal whendisintegration occurred in the LSI.
Conclusions. Since significantly less dilution and spreading occurredin the LSI, the exposure of the intestine to pharmaceutical excipientsand sCT was more concentrated resulting in a higher fraction of sCTabsorbed. The results of this study demonstrate that intestinal mixingkinetics have a dramatic impact on the ability of pharmaceuticalexcipients to modulate the oral bioavailability of peptide drugs like sCT.
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Lee, YH., Perry, B.A., Sutyak, J.P. et al. Regional Differences in Intestinal Spreading and pH Recovery and the Impact on Salmon Calcitonin Absorption in Dogs. Pharm Res 17, 284–290 (2000). https://doi.org/10.1023/A:1007596821702
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DOI: https://doi.org/10.1023/A:1007596821702