title: Transporter-targeted cholic acid-cytarabine conjugates for improved oral absorption.
abstract: 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 (40μM) showed potent antiproliferative activities (up to 70%) against HepG2 cells after incubation for 48h. The addition of bile acids could markedly reduce the antitumor activities of these conjugates. The N(4)-ursodeoxycholic acid conjugate of cytarabine (compound 5) exhibited optimal stability (t1/2=90min) 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.
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China; State Key Lab of New-tech for Chinese Medicine Pharmaceutical Processes, Lianyungang, 222001, China.
authors.forename: Dongpo
authors.initials: D
authors.lastname: Li
authors.affiliation: School of Pharmacy, China Medical University, Shenyang 110122, China. Electronic address: shanglei6677@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Shang
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China.
authors.forename: Zhonggui
authors.initials: Z
authors.lastname: He
authors.affiliation: Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, No. 103, Wenhua Road, Shenyang, 110016, China. Electronic address: sunjin66@21cn.com.
authors.forename: Jin
authors.initials: J
authors.lastname: Sun
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019826:Cholic Acid / Q000008:administration & dosage* / Q000378:metabolism*; D003561:Cytarabine / Q000008:administration & dosage* / Q000378:metabolism*; D016503:Drug Delivery Systems / Q000379:methods*; D065569:Gastrointestinal Absorption / Q000187:drug effects* / Q000502:physiology; D056945:Hep G2 Cells; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D026901:Membrane Transport Proteins; D003561:Cytarabine; D019826:Cholic Acid
keywords: Bile acid transporters; Cytarabine; Oral bioavailability; Prodrugs