Synthesis and Evaluation of Bile Acid–Ribavirin Conjugates as Prodrugs to Target the Liver

Abstract

Ribavirin is used to treat hepatitis C but causes serious hemolytic anemia. The objective of the study was to develop a ribavirin prodrug to achieve liver specific drug delivery and to reduce its off-target effect in red blood cells (RBC). The approach aimed to target the human sodium taurocholate cotransporting polypeptide (NTCP), which is a bile acid transporter predominately expressed in the liver. Six prodrugs with ribavirin conjugation at C-3 or C-24 of the bile acids were synthesized. In vitro uptake studies indicated that all six prodrugs were NTCP substrates. Metabolic studies in vitro indicated that ribavirin-L-Val-GCDCA was able to release ribavirin in the mouse liver S9 fraction. Additionally, in vitro studies showed that ribavirin in RBC was reduced by 16.7 fold from prodrug compared to parent drug incubation. Moreover, almost no prodrug was present in RBC. In vivo study in mice also showed that ribavirin-L-Val-GCDCA could provide almost the same ribavirin exposure in the liver as ribavirin administration, but with about 1.8-fold less exposure of ribavirin in RBC, plasma, and kidney. Overall, the study suggested that ribavirin-L-Val-GCDCA has the potential to achieve ribavirin specific liver delivery.

Enhanced Liver Targeting of Camptothecin via Conjugation with Deoxycholic Acid

“…It demonstrated that conjugation with deoxycholic acid increased liver targeting in vivo by 1.67-fold in comparison to CPT. This result was in accordance with previous report that conjugation with bile acid could increase liver targeting of ribavirin by 1.80-fold [16].…”

“…The prodrug strategy, applying bile acids as the modifying moieties to target hepatocyte transporters and thus obtain hepatic-targeting delivery agents, has been suggested in previous studies [14,15,16,17]. This prodrug approach takes advantage of the highly specific interaction of bile acid ligands with Na + -dependent taurocholate co-transporting polypeptide (NTCP) receptors which are specifically and abundantly expressed in hepatocytes [18,19,20].…”

A Minireview: Usefulness of Transporter-Targeted Prodrugs in Enhancing Membrane Permeability

“…The usefulness of prodrug-targeted NTCP as the drug delivery to the liver is also reported using floxuridine and ribavirin as parent drugs. 33,34 Carnitine Transporter L-Carnitine L-Carnitine is endogenously biosynthesized from Lys and Met in the liver and kidney of healthy human. L-Carnitine is also supplied from dietary foods and exhibits an important role in the production of energy by conjugating fatty acids for transport into the mitochondria.…”

Approaches of Prodrug Designing to Treat Cancer, Neurodegenerative Disorders and Viral Diseases

“…A study was performed whose main purpose was to synthesize a ribavirin prodrug to acquire liver-specific drug delivery. The main target of this approach was to work on human sodium taurocholate cotransporting polypeptide (NTCP) which is a bile acid transporter located in the liver (Dong et al, 2015).…”