基于寡肽转运体介导的紫杉醇小分子前体药物的制备及提高口服吸收效果的研究

Preparation of Paclitaxel Amino Acid Prodrug Based on Mechanism of Peptide Transporter PEPT1 Mediation and Study on Improvement of Intestinal Absorption

目的为了提高紫衫醇的口服生物利用度,本实验基于寡肽转运体介导设计了小分子紫杉醇前体药物。方法合成了紫杉醇-胱胺和紫杉醇-胱胺-缬氨酸两亲性前体药物。以细胞实验,考察了前体药物的膜透过能力。通过大鼠在体肠循环实验,考察了小分子前体药物的肠吸收机制。最后,对药物的口服药物动力学特征进行了研究。结果前体药物具有比较好的跨过细胞膜能力,大鼠在体肠循环实验表明,寡肽转运体对紫杉醇-胱胺-缬氨酸的跨膜转运具有明显地介导作用,极大提高其肠黏膜吸收能力。动物实验结果表明,与原料药组相比,紫杉醇-胱胺-缬氨酸组的绝对生物利用度从19.31%提高到了30.61%。结论寡肽转运体对紫杉醇-胱胺-缬氨酸小分子前药具有比较好的介导作用,极大提高了紫杉醇的口服生物利用度。

OBJECTIVE To improve oral bioavailability of paclitaxel,prepare small molecular paclitaxel prodrug.METHODS The paclitaxel-cystamine and paclitaxel-cystamine-valine amphiphilic prodrugs were synthesized.The membrane permeability of the prodrugs was verified by cell experiments.The in vivo absorption mechanism was investigated using in situ intestinal perfusion in rats.Finally,the oral pharmacokinetic characteristics of the prodrugs were studied.RESULTS The results showed that the prodrugs had a good ability to cross the cell membrane,and the in situ intestinal perfusion in rats showed that the peptide transporter PEPT1 had an obvious mediating effect on the trans-membrane transport of paclitaxel-cystamine-valine,which greatly improved the absorption capacity of intestinal mucosa.The results of animal experiments showed that the absolute bioavailability increased from 19.31%to 30.61%.CONCLUSION The peptide transporter PEPT1 has a good mediating effect on the small molecule prodrug,which greatly improves the oral bioavailability of paclitaxel.