Synthesis and in vitro evaluation of bile acid prodrugs of floxuridine to target the liver.
Int J Pharm
; 475(1-2): 597-604, 2014 Nov 20.
Article
en En
| MEDLINE
| ID: mdl-25219859
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Profármacos
/
Floxuridina
/
Hígado
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Int J Pharm
Año:
2014
Tipo del documento:
Article
País de afiliación:
Estados Unidos
Pais de publicación:
Países Bajos