In vivo and in vitro pharmacokinetics of 4,6-benzylidene-D-glucose (BG) in rats
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Summary
In vivo pharmacokinetics of 4,6-benzylidene-D-glucose (BG) was investigated in rats following an i.v. bolus injection of 85 mg BG/kg body weight. High performance liquid chromatography (HPLC) was used to characterize and quantitate BG in whole blood or serum samples. It was found that BG rapidly disappeared with a half-life (t1/2)on the order of 10 min. At the same time a metabolite appeared which eluted before the double isomer peaks of BG. It increased in concentration from 0 to 30 min after initial i.v. injection of BG. Thereafter the metabolite was slowly removed or cleared from the animals. The t1/2 of the metabolite calculated from the time of maximum concentration was found to be about 1 h. BG was also metabolized by whole rat blood at 37°C, but on a different time scale in vitro. The t1/2 of BG in the in vitro assays was now about 4 h, as compared to 10 min in vivo. BG was not metabolized in rat plasma or rat serum. In contrast to in vivo data, the metabolite of BG was not reduced upon further incubation, but remained in blood samples with no reduction for at least 24 h. In addition, we found that protein synthesis was inhibited by approximately 50% when isolated rat hepatocytes were incubated with 3.2 mM BG. BG was slowly metabolized by hepatocytes to produce a metabolite indistinguishable (by HPLC) from that found in blood samples. Analysis of the metabolite by combined gas chromatography-mass spectrometric (GC-MS) methods identified it as being 1,3-benzylidene-D-glucitol. An intracellular reduction of BG by aldose reductase is proposed to occur.
Key words
benzylidene-glucosem BG HPLC pharmacokineticsPreview
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References
- 1.Pettersen EO, Nome O, Rønning ØW, Oftebro R: Effects of benzaldehyde on survival and cell-cycle kinetics of human cells cultivated in vitro. Eur J Cancer Clin Oncol 19:507–514, 1983Google Scholar
- 2.Pettersen EO, Rønning ØW, Nome O, Oftebro R: Effects of benzaldehyde on protein metabolism of human cells cultivated in vitro. Eur J Cancer Clin Oncol 19:935–940, 1983Google Scholar
- 3.Takeuchi S, Kochi M, Sakaguchi K, Nakagawa K, Mizutani T: Benzaldehyde as a carcinostatic principle in figs. Agric Biol Chem 42:1449–1451, 1978Google Scholar
- 4.Miyakawa T, Zundel J-L, Sakaguchi K: Selective inhibitory effect of benzaldehyde on the growth of simian virus-transformed cells. Biochem Biophys Res Commun 87:1024–1030, 1979Google Scholar
- 5.Kochi M, Takeuchi S, Mizutani T, Mochizuki K, Matsumoto Y, Saito Y: Antitumor activity of benzaldehyde. Cancer Treat Rep 64:21–23, 1980Google Scholar
- 6.Takeuchi S, Kochi M, Kawarada A: Carcinostatics. Japanese Patent Laid Open No. 54-70428, 1979Google Scholar
- 7.Takeuchi S, Kochi M, Kawarada A: Carcinostatics. Japanese Patent Laid Open No. 60-155114, 1985Google Scholar
- 8.Kochi M, Amemiya K, Niwayama M: Antitumor activity of benzaldehyde derivative. Proc 13th Int Cancer Congress, Seattle, WA, USA, 1982, Abstract 1131Google Scholar
- 9.Pettersen EO, Dornish JM, Rønning ØW: 4,6-Benzylidene- D-glucose, a benzaldehyde derivative that inhibits protein synthesis but not mitosis of NHIK 3025 cells. Cancer Res 45:2085–2091, 1985Google Scholar
- 10.Taetle R, Howell SB: Preclinical re-evaluation of benzaldehyde as a chemotherapeutic agent. Cancer Treat Rep 67:561–566, 1983Google Scholar
- 11.Kochi M, Isono N, Miwayama M, Shirakabe K: Antitumor activity of a benzaldehyde derivative. Cancer Treat Rep 69:533–537, 1985Google Scholar
- 12.Tatsumura T, Nishide R, Koyama S, Ohba Y, Tsujimoto M, Yago O, Tsuda M, Sato H, Mori A, Yamamota K, Komori Y: Antitumor effect of 4,6-benzylidene-D-glucose in clinical studies. Proc Amer Soc Clin Oncol 6:142, 1987Google Scholar
- 13.Pettersen EO, Schwarze PE, Dornish JM, Nesland JM: Anti-tumor effect of benzylidene-glucose (BG) in rats with chemically induced hepatocellular carcinoma. Anticancer Res 6:147–152, 1986Google Scholar
- 14.Seglen PO: Preparation of isolated rat liver cells. Methods Cell Biol 13:29–83, 1976Google Scholar
- 15.Schwarze PE, Solheim AE, Seglen PO: Amino acid and energy requirements for rat hepatocytes in primary culture. In Vitro 18:43–54, 1982Google Scholar
- 16.Gordon PB, Seglen PO: Autophagic sequestration of [14C]sucrose introduced into rat hepatocytes by reversible electropermeabilization. Exp Cell Res 142:1–14, 1982Google Scholar
- 17.Sweeley CC, Bentley R, Makita M, Wells WW: Gas-liquid chromatography of trimethylsilyl derivatives of sugars and related substances. J Amer Chem Soc 85:2497–2502, 1963Google Scholar
- 18.Sweeley CC, Elliott WH, Fries I, Ryhage R: Mass spectrometric determination of unresolved components in gas chromatographic effluents. Anal Chem 38:1549–1553, 1966Google Scholar
- 19.Dornish JM, Pettersen EO, Nesland JM, Raabe N, Kochi M: Pharmacokinetics of 4,6-benzylidene-D-glucose (BG) in human cancer patients. Proc Amer Assoc Cancer Res 28:193, 1987Google Scholar
- 20.Srivastava SK, Ansari NH, Hair GA, Das B: Aldose and aldehyde reductases in human tissues. Biochim Biophys Acta 800:220–227, 1984Google Scholar
- 21.Das B, Srivastava SK: Purification and properties of aldose reductase and aldehyde reductase II from human erythrocyte. Arch Biochem Biophys 238:670–679, 1985Google Scholar