title: 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 (RBCs). 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-glycochenodeoxycholic acid (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 with 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.
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201.
authors: Zhongqi
authors: Z
authors: Dong
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201.
authors: Qing
authors: Q
authors: Li
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201.
authors: Dong
authors: D
authors: Guo
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201.
authors: Yan
authors: Y
authors: Shu
authors: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland, 21201.
authors: James E
authors: JE
authors: Polli
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry*; D001647:Bile Acids and Salts / Q000138:chemical synthesis / Q000737:chemistry*; D002460:Cell Line; D016503:Drug Delivery Systems; D004355:Drug Stability; D004912:Erythrocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D011355:Prodrugs; D012254:Ribavirin / Q000138:chemical synthesis / Q000737:chemistry*; D027981:Symporters / Q000378:metabolism
chemical_list: D000998:Antiviral Agents; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D011355:Prodrugs; D027981:Symporters; C071908:sodium-bile acid cotransporter; D012254:Ribavirin
keywords: NTCP; bile acid transporters; hepatocytes; metabolism; prodrugs; ribavirin; site-specific delivery
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