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Evaluation of Cell-Penetrating Peptides as Versatile, Effective Absorption Enhancers: Relation to Molecular Weight and Inherent Epithelial Drug Permeability

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Abstract

Purpose

The poor permeability of new drug candidates across intestinal epithelial membranes complicates their development in oral form. This study investigated the potential of cell-penetrating peptides (CPPs) to improve the intestinal permeation and absorption of low-permeable low-molecular-weight (low-MW) drugs.

Methods

The in vitro epithelial permeation of six different drugs (metformin, risedronate, zanamivir, methotrexate [MTX], tacrolimus, and vincristine [VCR]) across Caco-2 cell monolayers was examined in the presence and absence of L- or D-penetratin, and the correlation between permeation enhancement efficiency and the properties of tested drugs was analyzed. In addition, a rat closed ileal loop absorption study was conducted to determine the in vivo effects of penetratin.

Results

MTX and VCR efficiently permeated Caco-2 monolayers in the presence of L- and D-penetratin, suggesting that CPPs enhanced the epithelial permeation of drugs with relatively high molecular weight and resultant limited intrinsic permeability. The in vivo rat closed ileal loop absorption study revealed the stimulatory effect of L- and D-penetratin on the intestinal absorption of MTX and VCR.

Conclusions

CPPs are useful as oral absorption enhancers for low-permeable drugs.

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ACKNOWLEDGMENTS AND DISCLOSURES

Authors are grateful to Dr. Keizo Fukushima (Laboratory of Clinical Pharmacokinetics, Kobe Gakuin University) for his assistance in operation of LC-MS/MS. This research was supported in part by the Research Foundation for Pharmaceutical Sciences, JSPS KAKENHI Scientific Research (C) (16 K08211), and a Kobe Gakuin University Research Grant (A).

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Authors and Affiliations

  1. Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo, 650-8586, Japan

    Noriyasu Kamei, Jumpei Yamanaka, Yutaro Oda, Shohei Kaneoka, Yumeko Koide, Yuta Haruna, Yuta Takahashi, Hideyuki Tamiwa & Mariko Takeda-Morishita

Authors
  1. Noriyasu Kamei
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  2. Jumpei Yamanaka
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  6. Yuta Haruna
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Contributions

N.K. and M.T.-M. conceived and designed the study. N.K. and M.T.-M. acquired research grants. J.Y., Y.O., S.K., and Y.K. conducted transcellular transport study with Caco-2 cell monolayer. N.K., J.Y., Y. O., S.K., Y.K., and H.T. conducted the quantification of drug concentration by using LC-MS/MS and HPLC-UV. Y. H. and H.T. conducted in situ loop absorption experiments. N.K. prepared the manuscript. All authors analyzed and discussed the results and reviewed the manuscript.

Corresponding author

Correspondence to Mariko Takeda-Morishita.

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Kamei, N., Yamanaka, J., Oda, Y. et al. Evaluation of Cell-Penetrating Peptides as Versatile, Effective Absorption Enhancers: Relation to Molecular Weight and Inherent Epithelial Drug Permeability. Pharm Res 37, 182 (2020). https://doi.org/10.1007/s11095-020-02874-0

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  • DOI: https://doi.org/10.1007/s11095-020-02874-0

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