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Zhao C.,Shandong University | Li Y.,Shandong University | Qin Y.,Shandong University | Wang R.,Shandong University | And 4 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2013

Purpose: SL-01, dodecyl-3-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5- (hydroxymethyl)-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl) carbamoyl) pyrazine-2-carboxylate, is a prodrug of gemcitabine. Our previous reports suggested that SL-01 possesses superior bioavailability and anticancer activity to gemcitabine in mice. In this study, its pharmacokinetics and metabolisms were investigated in rats. Methods: The pharmacokinetics of SL-01 was studied following intravenous or oral administration of SL-01 to Sprague-Dawley rats. The metabolites profile of SL-01 was further determined in rats receiving intravenous administration of SL-01. Blood samples were analyzed by using LC-MS or LC-MS/MS assay. Results: Following administration with SL-01 intravenously or orally, SL-01, plasma gemcitabine released from SL-01 as well as the sum of gemcitabine (gemcitabine converted from SL-01 and plasma gemcitabine) exhibited higher values of V z /F and CL z /F, and longer MRT and t 1/2 than those of gemcitabine administered intravenously. The C max of gemcitabine produced by intravenous SL-01 was higher than that of gemcitabine dosed intravenously. The absolute bioavailability for the sum of gemcitabine was 32.2 % for intravenous and 22.2 % for oral administration with SL-01, respectively. After a single intravenous administration, a total of 5 components (M1, M2, M3, M4, and M5) were detected and identified as the metabolites of SL-01 in the plasma of rats. M1 and M2 were formed from the methylation and reduction of SL-01, respectively. Hydrolysis of the amide bond of SL-01 gave M3 and M4. M5 was produced from further dealkylation of M3. Conclusions: SL-01 displayed improved absorption, good distribution, high clearance, long mean residence time, and moderate bioavailability after administered intravenously or orally to rats. The major metabolic pathways of SL-01 involved methylation, reduction, hydrolysis, and dealkylation. These results suggested that SL-01 acts as a prodrug of gemcitabine in rats. © 2013 Springer-Verlag Berlin Heidelberg.


Zhao C.,Shandong University | Xue X.,Sanlugen PharmaTech Ltd. | Li G.,Sanlugen PharmaTech Ltd. | Sun C.,Shandong University | And 3 more authors.
Chemical Biology and Drug Design | Year: 2012

A series of oral prodrugs based on the structure of gemcitabine (2′,2′-difluorodeoxycytidine) were synthesised by introducing an amide group at the N4-position of the cytidine ring. A total of 16 compounds were obtained, and their chemical and biological characteristics were evaluated. The half-maximal inhibitory concentrations (IC50s) for most of these compounds were higher than that of gemcitabine in vitro. Compounds 5d and 5m, the representative compounds, were examined in terms of their physiological stabilities and pharmacokinetics. Compound 5d showed good stability in PBS and simulated intestinal fluid, and an analysis of its pharmacokinetics in mice suggested that the introduction of an amide group to gemcitabine could greatly improve its bioavailability. Further evaluation of compound 5din vivo showed that this compound possesses higher activity than gemcitabine against the growth of HepG2 human hepatocellular carcinoma cells and HCT-116 colon adenocarcinoma cells with less toxicity to animals. These results suggest that compound 5d could be further developed as a potential oral anticancer agent for clinical applications in which gemcitabine is currently used. A series of oral prodrugs based on the structure of gemcitabine were synthesized. Physiological and metabolic stabilities, pharmacokinetics and antitumor activities were evaluated for representative compounds. © 2012 John Wiley & Sons A/S.


Prodrugs based on gemcitabine structure shown in formula (I) as well as their synthetic method and application are disclosed in the present invention, wherein the definitions for the groups of a, b, c, d, E, Z and V are described in the specification. By modifying the N^(4 )group, the solubility, the bioavailability and the organ specificity of the prodrugs are improved. Therefore, the fast metabolism problem is overcome for the produced prodrugs compounds. Intestinal toxicity induced by gemcitabine is decreased. Thereby, the prodrugs can be delivered by oral administration in clinics and further improve their anti-tumor, anti-cancer, anti-infection and diffusion preventing capability, and can also specifically act on liver or colon. The synthetic method is simple and adapted to industrial production.


Prodrugs based on gemcitabine structure shown in formula (I) as well as their synthetic method and application are disclosed in the present invention, wherein the definitions for the groups of a, b, c, d, E, Z and V are described in the specification. By modifying the N^(4) group, the solubility, the bioavailability and the organ specificity of the prodrugs are improved. Therefore, the fast metabolism problem is overcome for the produced prodrugs compounds. Intestinal toxicity induced by gemcitabine is decreased. Thereby, the prodrugs can be delivered by oral administration in clinics and further improve their anti-tumor, anti-cancer, anti-infection and diffusion preventing capability, and can also specifically act on liver or colon. The synthetic method is simple and adapted to industrial production.

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