Synthesis and in vitro evaluation of bile acid prodrugs of floxuridine to target the liver

Floxuridine is often used to treat metastatic liver disease and is given as an infusion directly into the hepatic artery to increase the amount of intact drug that reaches the liver. The objective of this work was to design and synthesize prodrugs of floxuridine through conjugation to chenodeoxycholic acid (CDCA) to target the liver via the bile acid liver uptake transporter Na+/taurocholate cotransporting polypeptide (NTCP, SLC10A1). Two isomeric prodrugs of floxuridine were synthesized: floxuridine 3′glutamic acid–CDCA and floxuridine 5′-glutamic acid–CDCA. Both were potent inhibitors and substrates of NTCP. Floxuridine 3′glutamic acid–CDCA showed Ki = 6.86 ± 1.37 μM, Km = 10.7 ± 2.1 μM, and passive permeability = 0.663 (±0.121) × 10−7 cm/s while floxuridine 5′-glutamic acid–CDCA showed Ki = 0.397 ± 0.038 μM, Km = 40.4 ± 15.2 μM, and passive permeability = 1.72 (±0.18) × 10−7 cm/s. Floxuridine itself had a higher passively permeability of 7.54 (±0.45) × 10−7 cm/s in the same cell line, indicating that both prodrugs have the potential for lower non-specific effects than the drug alone. Prodrugs were stable in rat plasma (t = 3 h), but quickly released in rat liver s9 fraction, suggesting future in vivo evaluation.

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