Synthesis and in vitro evaluation of potential sustained release prodrugs via targeting ASBT

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-l, 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 822 mu M and normJ(max) was 0 0917 In 4 h, 69 4% and 26 9% of niacin was released from 1 mu M and 5 mu M of the conjugate in Caco-2 homogenate. respectively For the ketoprofen prodrug. K-t was 50.8 mu M and normJ(max) was 1.58. In 4 h, 5 94% and 3 73% of ketoprofen was released from 1 mu M and 5 mu M 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. (C) 2010 Elsevier B.V. All rights reserved.