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 8.22 μM and normJ max was 0.0917. In four hours, 69.4% and 26.9% of niacin was released from 1 μM and 5 μM of the conjugate in Caco-2 homogenate, respectively. For the ketoprofen prodrug, K t was 50.8 μM and normJ max was 1.58. In four hours, 5.94% and 3.73% of ketoprofen was released from 1 μM and 5 μM of the conjugate in Caco-2 homogenate, and 24.5% and 12.2% of ketoprofen was release in liver homogenate, respectively. In vitro results showed that these bile acid conjugates are potential prolonged release prodrugs with binding affinity for ASBT.

Structural requirements of bile acid transporters: C-3 and C-7 modifications of steroidal hydroxyl groups

“…ASBT also accommodates various drug-like single ring scaffolds with different substituents attached to the bile acid (Gonzalez et al, 2009; Rais et al, 2010a; Rais et al, 2010b; Zheng et al, 2010). Using C-24 bile acid linkage chemistry, bile acid-based prodrugs of gabapentin, ketoprofen, and niacin have been shown to be ASBT substrates (Rais et al, 2011; Zheng and Polli, 2010). In addition to this C-24 chemical space, the C-3 bile acid chemical space has also been explored, where various linkers and drugs have been conjugated to a bile acid at C-3, resulting in some prodrugs (Kramer et al, 1994;Swaan et al, 1997).…”

The solute carrier family 10 (SLC10): Beyond bile acid transport

“…Oral administration in rats of the antiviral drug acyclovir conjugated with CDCA via a valine linker, increased acyclovir bioavailability by two-fold compared to acyclovir alone (Tolle-Sander et al, 2004). In addition to this finding, Polli’s group and collaborators have recently reported potential prodrug candidates, by conjugation with BA, including a monoanionic gabapentin conjugate (Rais et al, 2011) and enzymatically stable ketoprofen and niacin conjugates, with potential use as sustained release prodrugs (Zheng and Polli, 2010). …”

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

“…This steady plasma concentration of compound 5 could be ascribed to the improved stability of the cholic acid-cytarabine conjugate and the sustained release of cytarabine (Zheng and Polli, 2010). More importantly, the AUC0-∞ of compound 5 (34857.0± 7578.0 ng · h/mL) was significantly higher than that of cytarabine (16603.7± 2627.2 ng · h/mL).…”