| Pharmacokinetics and metabolism of SL-01, a prodrug of gemcitabine, in rats. | |
MedLine Citation:
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PMID: 23564376 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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. |
Authors:
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Cuirong Zhao; Yuanyuan Li; Yizhuo Qin; Ruiqi Wang; Gang Li; Changjun Sun; Xianjun Qu; Wenbao Li |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-4-6 |
Journal Detail:
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Title: Cancer chemotherapy and pharmacology Volume: - ISSN: 1432-0843 ISO Abbreviation: Cancer Chemother. Pharmacol. Publication Date: 2013 Apr |
Date Detail:
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Created Date: 2013-4-8 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 7806519 Medline TA: Cancer Chemother Pharmacol Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Wen Hua Xi Rd, Jinan, 250012, China, xiaozhao511@163.com. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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