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.

中文翻译：

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评价细胞穿透肽作为多功能有效吸收增强剂：与分子量和固有的上皮药物渗透性的关系。

目的

新药候选物跨肠上皮膜的渗透性差使它们以口服形式发展。这项研究调查了细胞穿透肽（CPPs）改善低渗透性低分子量（low-MW）药物肠道渗透和吸收的潜力。

方法

在体外上皮的六个不同的药物（二甲双胍，利塞膦酸盐，扎那米韦，甲氨蝶呤[MTX]，他克莫司和长春新碱[VCR]）在Caco-2细胞单层在L-或d-穿膜肽的存在和不存在检查渗透分析了渗透增强效率与被测药物性能之间的相关性。此外，进行了大鼠回肠闭合回肠吸收研究，以确定渗透素的体内作用。

结果

在L-和D-渗透素的存在下，MTX和VCR有效地渗透了Caco-2单层，这表明CPPs增强了具有较高分子量的药物的上皮渗透性，并因此限制了固有的通透性。在体内大鼠回肠闭合回路的吸收研究揭示L-和的刺激作用d-穿膜上MTX和VCR的肠吸收。

结论

CPP可用作低渗透性药物的口服吸收促进剂。