Evaluation of Cell-Penetrating Peptides as Versatile, Effective Absorption Enhancers: Relation to Molecular Weight and I
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RESEARCH PAPER
Evaluation of Cell-Penetrating Peptides as Versatile, Effective Absorption Enhancers: Relation to Molecular Weight and Inherent Epithelial Drug Permeability Noriyasu Kamei 1 & Jumpei Yamanaka 1 & Yutaro Oda 1 & Shohei Kaneoka 1 & Yumeko Koide 1 & Yuta Haruna 1 & Yuta Takahashi 1 & Hideyuki Tamiwa 1 & Mariko Takeda-Morishita 1 Received: 18 April 2020 / Accepted: 2 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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-molecularweight (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 Lor 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.
KEY WORDS absorption enhancer . cell-penetrating peptide . epithelial permeation . intestinal absorption . low-absorbable drug
* Mariko Takeda-Morishita [email protected] 1
Laboratory of Drug Delivery Systems, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan
INTRODUCTION The recent progress in molecular biology and bioengineering has enabled us to develop highly bioactive macromolecular agents, such as peptides and proteins, as new therapeutic options. Low-molecular weight (MW) compounds are the main agents for pharmacotherapy because of their structural simplicity and low cost of production. The biopharmaceutical classification system (BCS) often categorizes recently developed drug candidates into class III or IV (1–3), both of which are characterized as low-permeable drugs. Poor permeability is often related to the drugs’ characteristics to be recognized as substrates by efflux transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) (4–8). Such poor pharmacokinetic properties complicate the development of such drugs in oral form, and most drug candidates are excluded before reaching the development stage. In addition to conventional low-MW drugs, midsize molecules ranging from ~800 to 2000
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