Document Detail

Pharmacokinetics and metabolism of SL-01, a prodrug of gemcitabine, in rats.
MedLine Citation:
PMID:  23564376     Owner:  NLM     Status:  Publisher    
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.
Cuirong Zhao; Yuanyuan Li; Yizhuo Qin; Ruiqi Wang; Gang Li; Changjun Sun; Xianjun Qu; Wenbao Li
Related Documents :
9553646 - Experimental autoimmune prostatitis: in vivo induction of the autoimmune response to ly...
20564206 - Castration induces changes in the cation-dependent mannose-6-phosphate receptor in rat ...
491776 - Testosterone metabolism by the prostate of the aging axc rat.
9065806 - Rat and human maspins: structures, metastatic suppressor activity and mutation in prost...
8301156 - The effect of interferon-gamma on rejection and neutrophil function following transplan...
10499866 - Age-related changes in thyroid hormone effects on glucose transporter isoforms of rat h...
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-4-6
Journal Detail:
Title:  Cancer chemotherapy and pharmacology     Volume:  -     ISSN:  1432-0843     ISO Abbreviation:  Cancer Chemother. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-4-8     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  7806519     Medline TA:  Cancer Chemother Pharmacol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Wen Hua Xi Rd, Jinan, 250012, China,
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Population PK/PD modeling of eltrombopag in subjects with advanced solid tumors with chemotherapy-in...
Next Document:  Bevacizumab and central nervous system (CNS) hemorrhage.