کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2484389 | 1114309 | 2015 | 13 صفحه PDF | دانلود رایگان |
![عکس صفحه اول مقاله: Synthesis and Evaluation of Bile Acid–Ribavirin Conjugates as Prodrugs to Target the Liver Synthesis and Evaluation of Bile Acid–Ribavirin Conjugates as Prodrugs to Target the Liver](/preview/png/2484389.png)
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.
Journal: Journal of Pharmaceutical Sciences - Volume 104, Issue 9, September 2015, Pages 2864–2876