Utilization of an In Situ Rat Absorption Model to Assess the Gut Permeability of Three Peptidic HIV-1 Protease Inhibitors
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Authors
Rop, Timothy J.
Issue Date
1992
Type
Thesis
Language
en_US
Keywords
Alternative Title
Abstract
Peptides represent a class of therapeutic pharmaceuticals with
great potential, as several peptidic HIV protease inhibitors with
molecular weights of approximately 800 to 1000 look especially
promising in the treatment of AIDS. Obstacles such as enzymatic
degradation, drug metabolism, and "first pass" liver clearance are
all important factors that reduce the oral bioavailability of such
peptides, but poor absorption across the intestinal epithelium is the
major barrier to effective oral administration.
Recent in vitro investigation disclosed a strong direct
correlation between the heptane-ethylene glycol partition
coefficients and the effective permeabilities across Caco-2 cells
for a series of six peptidic HIV-1 protease inhibitors. The findings
suggest that the major determinant of desolvation energy, and thus
peptide permeability to the gut wall, is not necessarily the number
of hydrogen bonding sites inherent in the structure of the peptide,
but more precisely the hydrogen bonding potential of these sites. An
in situ rat mesenteric vein absorption model was employed to verify
this relationship for three of the six peptidic inhibitors. Briefly, a
constant infusion was utilized to perfuse peptide solutions through
an isolated loop of gut while both the mesenteric blood exiting the
section and the intestinal perfusate were continuously collected.
Amounts of drug in both the perfusate and the blood were quantified
by HPLC to allow the calculation of both appearance and
disappearance permeabilities. Neither appearance nor disappearance
permeability coefficients support the relationship found in vitro
between the heptane-ethylene glycol partition coefficient and
peptide permeability. Further investigation is required to confirm
this finding and to interpret its significance.
Description
v, 42 p.
Citation
Publisher
Kalamazoo College
License
U.S. copyright laws protect this material. Commercial use or distribution of this material is not permitted without prior written permission of the copyright holder.