Synthesis and characterization of new liver targeting 5-fluorouracil-cholic acid conjugates.
The objective of this work was to develop a liver-specific antihepato carcinoma agent. A series of 5-fluorouracil / cholic acid conjugates (5-FU-cholic acid conjugates) were prepared and tested for their chemical characteristics and bio-distribution properties. The in-vitro stability trial showed 5-FU-cholic acid conjugates could be completely hydrolyzed by heating at 70 degrees C in an acidic solution, pH = 1, for 5 min. The fast and complete hydrolysis of these compounds could be compatible with a fast separation and analysis method to shorten the analysis time. The decomposition speeds of the 5-FU-cholic acid conjugates in different organs of mice at several time points after oral administration were evaluated by measuring the concentrations of regenerated 5-FU in organ tissue. The results were compared with those of the controls, which was a group of mice orally taking 5-FU. The concentrations of 5-FU in mice liver tissue were remarkably increased after oral administration of the prodrugs, and were much larger than if only orally administered 5-FU. The results suggested the feasibility to improve therapeutic efficiency of liver targeting treatments by using cholic acid as the vector of drugs.
Qian
Shan
S
Key Laboratory of Drug Targeting, West China School of Pharmacy, Sichuan University, Sichuan, P.R. China.
Wu
Jian-Bo
JB
Wu
Xiao-Chun
XC
Li
Jie
J
Wu
Yong
Y
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D019826:Cholic Acid / Q000737:chemistry / Q000493:pharmacokinetics; D016503:Drug Delivery Systems / Q000379:methods*; D005260:Female; D005472:Fluorouracil / Q000737:chemistry / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects*; D051379:Mice; D015394:Molecular Structure; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
D000970:Antineoplastic Agents; D011355:Prodrugs; D019826:Cholic Acid; D005472:Fluorouracil