Transporter-targeted cholic acid-cytarabine conjugates for improved oral absorption

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• 作者：Dong Zhang^a ; ¹ ; Dongpo Li^a ; ^b ; ¹ ; Lei Shang^c ; ^{shanglei6677@163.com" class="auth_mail" title="E-mail the corresponding author} ; Zhonggui He^a ; Jin Sun^a ; ^{sunjin66@21cn.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Cytarabine ; Bile acid transporters ; Prodrugs ; Oral bioavailability
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：10 September 2016
• 年：2016
• 卷：511
• 期：1
• 页码：161-169
• 全文大小：1370 K

文摘

Cytarabine has a poor oral absorption due to its rapid deamination and poor membrane permeability. Bile acid transporters are highly expressed both in enterocytes and hepatocytes and to increase the oral bioavailability and investigate the potential application of cytarabine for liver cancers, a transporter- recognizing prodrug strategy was applied to design and synthesize four conjugates of cytarabine with cholic acid (CA), chenodeoxycholic acid (CDCA), hyodeoxycholic acid (HDCA) and ursodeoxycholic acid (UDCA). The anticancer activities against HepG2 cells were evaluated by MTT assay and the role of bile acid transporters during cellular transport was investigated in a competitive inhibition experiment. The in vitro and in vivo metabolic stabilities of these conjugates were studied in rat plasma and liver homogenates. Finally, an oral bioavailability study was conducted in rats. All the cholic acid-cytarabine conjugates (40 μM) showed potent antiproliferative activities (up to 70%) against HepG2 cells after incubation for 48 h. The addition of bile acids could markedly reduce the antitumor activities of these conjugates. The N⁴-ursodeoxycholic acid conjugate of cytarabine (compound 5) exhibited optimal stability (t_1/2 = 90 min) in vitro and a 3.9-fold prolonged half-life of cytarabine in vivo. More importantly, compound 5 increased the oral bioavailability 2-fold compared with cytarabine. The results of the present study suggest that the prodrug strategy based on the bile acid transporters is suitable for improving the oral absorption and the clinical application of cytarabine.