PDF(Pubmed)
Abstract：
Doxorubicin is a potent chemotherapy drug, but its oral bioavailability is limited due to its low membrane permeability. Thus, absorption enhancers such as zonula occludens toxin and its six-mer fragment, FCIGRL, have been studied to address this issue. This study aimed to evaluate the effectiveness of four peptides (Pep1, Pep2, Pep3, and Pep4) derived from FCIGRL and investigate the changes in the absorption of doxorubicin, to propose an absorption enhancer for doxorubicin. Pep1 is a modified version of FCIGRL in which the hydroxyl group at the C-terminus is replaced with an amino group. Pep2 is a modified Pep1 in which cysteine is replaced with N3-substituted dipropionic acid. Pep3 and Pep4 are Pep2-modified homodimers. Pharmacokinetic analysis was performed in rats after the intraduodenal administration of doxorubicin solutions containing each FCIGRL-modified peptide and the stabilizer levan or benzalkonium chloride (BC). The results showed that Pep3 and Pep4 administered with levan each significantly increased the intestinal absorption of doxorubicin, as did Pep2 administered with levan/BC. In particular, 10 mg·kg-1 of Pep4 with levan significantly increased the area under the curve (AUC)0-240min of doxorubicin by 2.38-fold (p < 0.01) and the peak concentration (Cmax) by 3.30-fold (p < 0.01) compared to the control solution. The study findings indicate that Pep2, Pep3, and primarily Pep4 are novel absorption enhancers that can open tight junctions for doxorubicin, and the effectiveness of the peptides was directly affected by the presence of levan or levan/BC.
摘要：
阿霉素是一种有效的化疗药物，但由于其膜通透性低，其口服生物利用度有限。因此，吸收增强剂，如包合带毒素及其六聚体片段，FCIGRL,已经研究了这个问题。本研究旨在评估来自FCIGRL的四种肽（Pep1，Pep2，Pep3和Pep4）的有效性，并研究阿霉素吸收的变化，提出阿霉素的吸收促进剂。Pep1是FCIGRL的修饰形式,其中C-末端的羟基被氨基取代。Pep2是修饰的Pep1,其中半胱氨酸被N3取代的二丙酸取代。Pep3和Pep4是Pep2修饰的同二聚体。在十二指肠内施用含有每种FCIGRL修饰的肽和稳定剂果聚糖或苯扎氯铵（BC）的多柔比星溶液后，在大鼠中进行药代动力学分析。结果表明，Pep3和Pep4分别与左旋多糖一起施用能显著增加阿霉素的肠道吸收，Pep2与levan/BC一起施用。特别是,10mg·kg-1的Pep4和果聚糖显着增加了阿霉素的曲线下面积（AUC）0-240min，增加了2.38倍（p<0.01），峰浓度（Cmax）增加了3.30倍（p<0.01）与对照溶液相比。研究结果表明，Pep2，Pep3，主要是Pep4是新型的吸收增强剂，可以打开阿霉素的紧密连接，并且肽的有效性直接受到果聚糖或果聚糖/BC的存在的影响。
