Permeation enhancement of octreotide by specific bile salts in rats and human subjects: in vitro, in vivo correlations

Abstract

1 The potential of bile salts to improve the enteral absorption of octreotide, an orally active somatostatin analogue, was investigated by a combination of in vitro, in situ and in vivo experiments. 2 Incorporation of octreotide into lipid monolayers (as measured by area increase of the monolayer at constant surface pressure using a Langmuir-Blodgett trough set-up) depended on the type of bile salt used for monolayer pre-treatment. Addition of 20 gM octreotide to the subphase containing 20 gM of the dihydroxylated bile salt ursodeoxycholate (UDCA) causes a 9% increase in area, whereas addition of octreotide to the subphase containing the 7a-enantiomer of UDCA, chenodeoxycholate (CDCA), resulted in an area increase of the lipid monolayer of 20%. Area increase by octreotide alone was not significantly different from the increase of octreotide and UDCA in combination. 3 CDCA and UDCA in combination with octreotide increased the permeability of liposomal membranes for rubidium ions, whereas octreotide alone did not significantly change the permeability. This indicates membrane distortion as a possible cause for the enhanced absorption of octreotide by bile salts. 4 In polarized Caco-2 cell monolayers octreotide exhibited a permeation coefficient of 0.008 + 0.004 cm h-'. Addition of 0.2-1% of UDCA to the apical incubation medium had no significant effect upon the permeation coefficient. In contrast, 0.2-1% CDCA in the incubation medium resulted in a significant increase (P<0.05) of the monolayer permeability of octreotide (0.015-0.037 cm h-').5 Octreotide was absorbed as the intact peptide from the gastrointestinal tract in rats with an absorption efficiency of 0.26%. Coadministration of bile salt resulted in a dose-dependent increase in absorption efficiency of the peptide up to 20.2%. The observed effect was more pronounced for CDCA than for UDCA. 6 The effect of CDCA and UDCA on octreotide absorption in vivo was assessed in a pharmacokinetic study with healthy volunteers. After oral administration of 4 mg octreotide in the presence of 100 mg bile salt, an average bioavailability of the peptide of 1.26% was achieved in the presence of CDCA, whereas in the presence of UDCA a bioavailability of only 0.13% was reached. This difference was statistically significant (P <0.01). 7 In conclusion, the co-administration of CDCA is able to enhance the enteral absorption of octreotide. The in vitro and in situ experiments were predictive for the observed effect in human subjects.

Intestinal permeation enhancers for oral peptide delivery

“…Jejunal instillation of ursodeoxycholate (10 mg) increased F ABS of octreotide from 0.3% to 4.9% in rats [90]. Enhancement was associated with a time and concentration dependent release of LDH in Caco-2 suggesting a transcellular mechanism.…”

“…These include a range of natural-, semi-synthetic-and synthetic substances: solvents (e.g. ethanol [87]) to chelating agents (EDTA [88]), surfactants (sodium caprate (C 10 ) [89]), endogenous secretions (bile salts [90]), drugs (acetylsalicylic acid [91]), and high MW polymers (e.g. polysaccharides [92]) and bacterial toxins [93]).…”

“…Peptide sequences that correspond to the first extracellular loop motif of occludin (OP , OP and OP [90][91][92][93][94][95][96][97][98][99][100][101][102][103] ) can scramble homophilic interactions between adjacent epithelial cells and improve intestinal permeability [101]. However, even the shortest occludin peptide (OP [90][91][92][93][94][95][96][97][98][99][100][101][102][103] was only active when added bilaterally (68-fold benefit) or basolaterally (11-fold benefit) to epithelial monolayers on Transwells®.…”

“…Peptide sequences that correspond to the first extracellular loop motif of occludin (OP , OP and OP [90][91][92][93][94][95][96][97][98][99][100][101][102][103] ) can scramble homophilic interactions between adjacent epithelial cells and improve intestinal permeability [101]. However, even the shortest occludin peptide (OP [90][91][92][93][94][95][96][97][98][99][100][101][102][103] was only active when added bilaterally (68-fold benefit) or basolaterally (11-fold benefit) to epithelial monolayers on Transwells®. Efficacy (enzymatic/physical stability, targeting) of OP [90][91][92][93][94][95][96][97][98][99][100][101][102][103] was improved by synthesis of an all D-form, inclusion of peptidase inhibitors, and conjugation to a hydrocarbon moiety (C 14 -OP [90][91]...…”

Improving the absorption of earthworm fibrinolytic enzymes with mucosal enhancers

“…Although Caco-2 cells lack some protecting properties of the intestinal tissue (e.g., mucus, dilution effects), correspondence of in vitro and in vivo data were reported by several authors (Anderberg et al, 1992;Fricker et al, 1996).…”