title: Synthesis and in vitro evaluation of potential sustained release prodrugs via targeting ASBT.
abstract: The objective was to synthesize prodrugs of niacin and ketoprofen that target the human apical sodium-dependent bile acid transporter (ASBT) and potentially allow for prolonged drug release. Each drug was conjugated to the naturally occurring bile acid chenodeoxycholic acid (CDCA) using lysine as a linker. Their inhibitory binding and transport properties were evaluated in stably transfected ASBT-MDCK monolayers, and the kinetic parameters K(i), K(t), normJ(max), and P(p) were characterized. Enzymatic stability of the conjugates was evaluated in Caco-2 and liver homogenate. Both conjugates were potent inhibitors of ASBT. For the niacin prodrug, substrate kinetic parameter K(t) was 8.22microM and normJ(max) was 0.0917. In 4h, 69.4% and 26.9% of niacin was released from 1microM and 5microM of the conjugate in Caco-2 homogenate, respectively. For the ketoprofen prodrug, K(t) was 50.8microM and normJ(max) was 1.58. In 4h, 5.94% and 3.73% of ketoprofen was released from 1microM and 5microM of the conjugate in Caco-2 homogenate, and 24.5% and 12.2% of ketoprofen was released in liver homogenate, respectively. In vitro results showed that these bile acid conjugates are potential prolonged release prodrugs with binding affinity for ASBT.
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD 21201, United States.
authors.forename: Xiaowan
authors.initials: X
authors.lastname: Zheng
authors.forename: James E
authors.initials: JE
authors.lastname: Polli
mesh_terms: D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D002626:Chemistry, Pharmaceutical; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*; D003692:Delayed-Action Preparations; D004285:Dogs; D004337:Drug Carriers; D004339:Drug Compounding; D004355:Drug Stability; D006801:Humans; D006868:Hydrolysis; D007660:Ketoprofen / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000378:metabolism*; D008239:Lysine / Q000031:analogs & derivatives / Q000138:chemical synthesis; D009525:Niacin / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D011355:Prodrugs / Q000138:chemical synthesis / Q000378:metabolism*; D051381:Rats; D012995:Solubility; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D013656:Taurocholic Acid / Q000378:metabolism; D013678:Technology, Pharmaceutical / Q000379:methods; D014162:Transfection
chemical_list: D003692:Delayed-Action Preparations; D004337:Drug Carriers; D029363:Organic Anion Transporters, Sodium-Dependent; D011355:Prodrugs; D027981:Symporters; D002635:Chenodeoxycholic Acid; C071908:sodium-bile acid cotransporter; D009525:Niacin; D013656:Taurocholic Acid; D007660:Ketoprofen; D008239:Lysine