Pharmacokinetics and metabolism of SL-01, a prodrug of gemcitabine, in rats

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• 作者：Cuirong Zhao (1)
  Yuanyuan Li (1)
  Yizhuo Qin (1)
  Ruiqi Wang (1)
  Gang Li (2)
  Changjun Sun (2)
  Xianjun Qu (1)
  Wenbao Li (2)
  
• 关键词：SL ; 01 ; Pharmacokinetics ; Metabolism ; Prodrug ; Gemcitabine
• 刊名：Cancer Chemotherapy and Pharmacology
• 出版年：2013
• 出版时间：June 2013
• 年：2013
• 卷：71
• 期：6
• 页码：1541-1550
• 全文大小：627KB
• 参考文献：1. Hertel LW, Boder GB, Kroin JS, Rinzel SM, Poore GA, Todd GC, Grindey GB (1990) Evaluation of the antitumor activity of gemcitabine (2-2-difluoro-2-deoxycytidine). Cancer Res 50:4417-422
  2. Guchelaar HJ, Richel DJ, van Knapen A (1996) Clinical, toxicological and pharmacological aspects of gemcitabine. Cancer Treat Rev 22:15-1 CrossRef
  3. Toschi L, Finocchiaro G, Bartolini S, Gioia V, Cappuzzo F (2005) Role of gemcitabine in cancer therapy. Future Oncol 1:7-7 CrossRef
  4. Veltkamp SA, Jansen RS, Callies S, Pluim D, Visseren-Grul CM, Rosing H, Kloeker-Rhoades S, Andre VA, Beijnen JH, Slapak CA, Schellens JH (2008) Oral administration of gemcitabine in patients with refractory tumors: a clinical and pharmacologic study. Clin Cancer Res 14:3477-486 CrossRef
  5. Kroep J, van Moorsel C, Veerman G, Voorn D, Schultz R, Worzalla J, Tanzer L, Merriman R, Pinedo H, Peters G (1998) Role of deoxycytidine kinase (dCK), thymidine kinase 2 (TK2), and deoxycytidine deaminase (dCDA) in the antitumor activity of gemcitabine (dFdC). Adv Exp Med Biol 431:657-60 CrossRef
  6. Shipley L, Brown T, Cornpropst J, Hamilton M, Daniels W, Culp H (1992) Metabolism and disposition of gemcitabine, and oncolytic deoxycytidine analog, in mice, rats, and dogs. Drug Metab Dispos 20:849-55
  7. Iwata K, Aizawa K, Sakai S, Jingami S, Fukunaga E, Yoshida M, Hamada A, Saito H (2011) The relationship between treatment time of gemcitabine and development of hematologic toxicity in cancer patients. Biol Pharm Bull 34:1765-768 CrossRef
  8. Huang J, Robertson JM, Ye H, Margolis J, Nadeau L, Yan D (2012) Dose-volume analysis of predictors for gastrointestinal toxicity after concurrent full-dose gemcitabine and radiotherapy for locally advanced pancreatic adenocarcinoma. Int J Radiat Oncol Biol Phys 83:1120-125 CrossRef
  9. Han HK, Amidon GL (2000) Targeted prodrug design to optimize drug delivery. AAPS Pharm Sci 2:48-8 CrossRef
  10. Stella VJ (2010) Prodrugs: some thoughts and current issues. J Pharm Sci 99:4755-765 CrossRef
  11. Zhao CR, Xue XX, Li G, Sun CJ, Sun CC, Qu XJ, Li WB (2012) Synthesis and biological evaluation of oral prodrugs based on the structure of gemcitabine. Chem Biol Drug Des 80:479-88 CrossRef
  12. Xue XX, Li G, Sun CJ, Li WB (2009) Prodrugs based on gemcitabine structure as well as synthetic methods and the applications thereof. China Patent CN101525361A
  13. Bender DM, Bao J, Dantzig AH, Diseroad WD, Law KL, Magnus NA, Peterson JA, Perkins EJ, Pu YJ, Reutzel-Edens SM, Remick DM, Starling JJ, Stephenson GA, Vaid RK, Zhang D, McCarthy JR (2009) Synthesis, crystallization, and biological evaluation of an orally active prodrug of gemcitabine. J Med Chem 52:6958-961 CrossRef
  14. Zhao CR, Yue B, Liu HP, Sun CC, Li WB, Qu XJ (2012) SL-01, an oral gemcitabine derivative, inhibited human cancer growth more potently than gemcitabine. Toxicol Appl Pharmacol 262:293-00 CrossRef
  15. Wang H, Zhu QW, Ye P, Li ZB, Li Y, Cao ZL, Shen L (2012) Pioglitazone attenuates myocardial ischemia-reperfusion injury via up-regulation of ERK and COX-2. Biosci Trends 6:325-32
  16. Zhao T, Yang Y, Zong A, Tan H, Song X, Meng S, Song C, Pang G, Wang F (2012) N-terminal PEGylation of human serum albumin and investigation of its pharmacokinetics and pulmonary microvascular retention. Biosci Trends 6:81-8
  17. Kaushal G, Shao J (2009) Vaginal delivery of protein drugs in rats by gene-transformed / Lactococcus lactis. Drug Discov Ther 3:228-33
  18. Davies B, Morris T (1993) Physiological parameters in laboratory animals and humans. Pharm Res 10:1093-095 CrossRef
  
• 作者单位：Cuirong Zhao (1)
  Yuanyuan Li (1)
  Yizhuo Qin (1)
  Ruiqi Wang (1)
  Gang Li (2)
  Changjun Sun (2)
  Xianjun Qu (1)
  Wenbao Li (2)
  
  1. Department of Pharmacology, School of Pharmaceutical Sciences, Shandong University, Wen Hua Xi Rd, Jinan, 250012, China
  2. Sanlugen PharmaTech Ltd., 2766 Yingxiu Road, Jinan, 250101, China
  
• ISSN：1432-0843

文摘

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.