Absorption Mechanism of a Physical Complex of Monomeric
Insulin and Deoxycholyl‑l‑lysyl-methylester
in the Small Intestine
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Abstract
Currently, oral administration of
insulin still remains the best
option to avoid the burden of repeated subcutaneous injections and
to improve its pharmacokinetics. The objective of the present investigation
was to demonstrate the absorption mechanism of insulin in the physical
complexation of deoxycholyl-l-lysyl-methylester (DCK) for
oral delivery. The oral insulin/DCK complex was prepared by making
a physical complex of insulin aspart with DCK through ion-pair interaction
in water. For the cellular uptake study, fluorescein-labeled insulin
or DCK were prepared according to a standard protocol and applied
to Caco-2 or MDCK cell lines. For the PK/PD studies, we performed
intrajejunal administration of different formulation of insulin/DCK
complex to diabetic rats. The resulting insulin and DCK complex demonstrated
greatly enhanced lipophilicity as well as increased permeation across
Caco-2 monolayers. The immunofluorescence study revealed the distribution
of the complex in the cytoplasm of Caco-2 cells. Moreover, in the
apical sodium bile acid transporter (ASBT) transfected MDCK, the insulin/DCK
complex showed interaction with ASBT, and also demonstrated absorption
through passive diffusion. We could not find that any evidence of
endocytosis in relation to the uptake of insulin complex in vitro.
In the rat intestine model, the highest absorption of insulin complex
was observed in the jejunum at 1 h and then in the ileum at 2–4
h. In PK/PD study, the complex showed a similar PK profile to that
of SC insulin. Overall, the study showed that the effect of DCK on
enhancing the absorption of insulin resulted from transcellular processes
as well as bile acid transporter activity