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  • 1
    Electronic Resource
    Electronic Resource
    Regional Differences in Intestinal Spreading and pH Recovery and the Impact on Salmon Calcitonin Absorption in Dogs (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 284-290 
    Details
    ISSN: 1573-904X
    Keywords: intestinal motility ; regional pH ; oral absorption ; peptide drugs ; salmon calcitonin ; IAP dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: 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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007596821702
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    Paper (German National Licenses)
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  • 2
    Electronic Resource
    Electronic Resource
    Impact of Regional Intestinal pH Modulation on Absorption of Peptide Drugs: Oral Absorption Studies of Salmon Calcitonin in Beagle Dogs (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1233-1239 
    Details
    ISSN: 1573-904X
    Keywords: intestinal pH recovery ; oral absorption ; peptide drugs ; salmon calcitonin ; dogs
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. 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 (tpH,min) and time to reach the peak plasma concentration (tconc,max) of sCT (tconc,max = 0.95 × tpH,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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1014849630520
    Library Location Call Number Volume/Issue/Year Availability
    BibTip Others were also interested in ...
    Paper (German National Licenses)
    Fulltext
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