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Mucins are Involved in the Intestinal Permeation of Lipophilic Drugs in the Proximal Region of Rat Small Intestine

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Abstract

Purpose

Mucins are the principal glycoproteins in mucus and have been implicated in the limitation of intestinal drug absorption; however, the contribution of these molecules to intestinal drug absorption remains unclear. In this study, the relationship between the effect of the mucus layer on intestinal drug permeation and mucin distribution in different parts of the rat gastrointestinal tract was evaluated.

Methods

The intestinal permeability of various lipophilic drugs in rat small intestine was evaluated using the in vitro sac method. The expression profiles of mucin mRNA and proteins were evaluated by quantitative real-time RT-PCR and western blotting, respectively.

Results

The intestinal permeability of griseofulvin and antipyrine was enhanced by dithiothreitol (DTT) treatment in the proximal small intestine, such as duodenum and jejunum, but not in the distal regions. The mRNA expression analysis of rat mucin genes revealed that the intestinal expression of Muc5ac was considerably higher in the duodenum, whereas that of Muc1, Muc2, and Muc3A was gradually increased toward the lower intestine. In addition, Muc5ac protein was detected only in the luminal fluids from the proximal small intestine after DTT treatment.

Conclusions

Mucus limits the intestinal permeation of lipophilic drugs in the rat proximal small intestine, in which Muc5ac may be involved.

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Abbreviations

DTT :

Dithiothreitol

FD-4 :

Fluorescein isothiocyanate-dextran 4000

Gapdh :

Glyceraldehyde-3-phosphate dehydrogenase

KHB :

Krebs–Henseleit bicarbonate

P app :

Apparent permeability coefficient

qPCR :

Quantitative real-time RT-PCR

UWL :

Unstirred water layer

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Acknowledgments and Disclosures

This work was supported by a research grant from The Nakatomi Foundation and JSPS KAKENHI (Grant Number 17 K15522).

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Author notes

  1. Kaori Miyazaki and Hisanao Kishimoto contributed equally to this work.

Authors and Affiliations

  1. Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, 1432-1, Horinouchi, Hachioji, Tokyo, 192-0392, Japan

    Kaori Miyazaki, Hisanao Kishimoto, Miho Muratani, Hanai Kobayashi, Yoshiyuki Shirasaka & Katsuhisa Inoue

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  1. Kaori Miyazaki
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  2. Hisanao Kishimoto
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  3. Miho Muratani
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  6. Katsuhisa Inoue
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Correspondence to Katsuhisa Inoue.

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Miyazaki, K., Kishimoto, H., Muratani, M. et al. Mucins are Involved in the Intestinal Permeation of Lipophilic Drugs in the Proximal Region of Rat Small Intestine. Pharm Res 36, 162 (2019). https://doi.org/10.1007/s11095-019-2701-9

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