Impact of regional intestinal pH modulation on absorption of peptide drugs: Oral absorption studies of salmon calcitonin in beagle dogs

Purpose. To investigate the relationship between the modulation of intestin al pH and the oral absorption properties of a model peptide drug, salmon ca lcitonin (sCT), in conscious beagle dogs. Methods. Studies were performed to characterize the disintegration of the f ormulation, intestinal pH changes, and the appearance of the peptide in the blood. Enteric-coated formulations containing sCT and various amounts of c itric acid (CA) were tethered to a Heidelberg capsule (HC) and given orally to normal beagle dogs. Blood samples were collected and analyzed by radioi mmunoassay (RIA). Intestinal pH was continuously monitored using the Heidel berg pH capsule (HC) system. The integrity of the HC-delivery system tether was verified by fluoroscopy. Results. The intra-individual variation in gastric emptying (GE) of the del ivery system was large. There were also large inter-individual differences in the disintegration and absorption properties of the various formulations . However, the peak plasma concentrations of sCT were always observed when the intestinal pH declined. The average baseline intestinal pH was 6.1 +/- 0.2 (mean +/- SEM, n = 12). The intestinal pH reduction was 2.6 +/- 0.4 (me an +/- SEM, n = 12, ranged from 0.5 to 4.0 units from baseline). There was a good correlation between the time to reach the trough intestinal pH (t(pH ,min)) and time to reach the peak plasma concentration (t(cone,max)) of sCT (t(cone,max) = 0.95 X t(pH,min) + 14.1, n = 11, r(2) = 0.91). Plasma C-max and area under the curve (AUC) increased with increasing amounts of CA in the formulations. Conclusions. The results of these studies demonstrate that the oral absorpt ion properties of a model peptide drug, sCT, can be modulated by changing i ntestinal pH. sCT is a substrate for the pancreatic serine protease trypsin which has maximal activity at pH 5 to 6. Reducing intestinal pH presumably stabilizes sCT in the GI tract enabling greater absorption of the intact p eptide.