Impact of regional intestinal pH modulation on absorption of peptide drugs: oral absorption studies of salmon calcitonin in beagle dogs.
OBJECTIVE
To investigate the relationship between the modulation of intestinal pH and the oral absorption properties of a model peptide drug, salmon calcitonin (sCT), in conscious beagle dogs.


METHODS
Studies were performed to characterize the disintegration of the formulation, intestinal pH changes, and the appearance of the peptide in the blood. Enteric-coated formulations containing sCT and various amounts of citric acid (CA) were tethered to a Heidelberg capsule (HC) and given orally to normal beagle dogs. Blood samples were collected and analyzed by radioimmunoassay (RIA). Intestinal pH was continuously monitored using the Heidelberg 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 delivery 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 (mean +/- 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 (tconc,max)) of sCT (t(conc,max) = 0.95 x t(pH,min) + 14.1, n = 11, r2 = 0.91). Plasma Cmax 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 absorption properties of a model peptide drug, sCT, can be modulated by changing intestinal 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 peptide.
Lee
Y H
YH
Department of Pharmaceutics, College of Pharmacy, Rutgers--The State University of New Jersey, Piscataway 08854, USA.
Perry
B A
BA
Labruno
S
S
Lee
H S
HS
Stern
W
W
Falzone
L M
LM
Sinko
P J
PJ
D000042:Absorption; D000284:Administration, Oral; D000818:Animals; D002116:Calcitonin / Q000493:pharmacokinetics*; D004285:Dogs; D005746:Gastric Emptying; D006863:Hydrogen-Ion Concentration; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D009055:Mouth / Q000378:metabolism*
C028815:salmon calcitonin; D002116:Calcitonin