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DOI: 10.1055/s-2008-1034307
© Georg Thieme Verlag KG Stuttgart · New York
Pharmacokinetics and Tissue Distribution of a Water-Soluble Flavonol Triglycoside, CTN986, in Mice
Publikationsverlauf
Received: October 17, 2007
Revised: November 30, 2007
Accepted: January 14, 2008
Publikationsdatum:
08. Februar 2008 (online)
![](https://www.thieme-connect.de/media/plantamedica/200803/lookinside/thumbnails/10.1055-s-2008-1034307-1.jpg)
Abstract
The pharmacokinetics and bioavailability of CTN986, a highly water-soluble flavonol triglycoside that has shown interesting antidepressant effects, were determined in mice after intravenous (i. v.), intraperitoneal (i. p.) and oral administrations. Concentrations of CTN986 in the biological samples were determined by a validated LC/MS/MS method. Non-compartmental methods were used to perform pharmacokinetic data analysis. The dose-dependent pharmacokinetics of CTN986 was characterized after i. v. administrations (0.16, 0.4 and 1.0 mg/kg) to mice. There was no significant difference in clearance (CL) with increasing dose [252.66 ± 42.82 mL/h (0.16 mg/kg) versus 241.73 ± 14.93 mL/h (1.0 mg/kg)] after i. v. administrations. The absolute bioavailability of CTN986 after i. p. and oral administrations was 96.57 % and 1.31 %, respectively. CTN986 was found to distribute widely in the internal organs of mice 10 min after oral dosage, with tissue concentrations in the order of duodenum, stomach, small intestine, kidney, lung, liver, brain, heart and spleen (from the highest to the lowest). In conclusion, CTN986 could be absorbed and extensively distributed into tissues as its intact form in mice.
Key words
CTN986 - flavonol triglycoside - pharmacokinetics - tissue distribution
References
- 1 Mattila P, Astola J, Kumpulainen J. Determination of flavonoids in plant material by HPLC with diode-array and electro-array detections. J Agric Food Chem. 2000; 48 5834-41
- 2 Rice-Evans C A, Miller N J, Paganga G. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic Biol Med. 1996; 20 933-56
- 3 Butterweck V, Jurgenliemk G, Nahrstedt A, Winterhoff H. Flavonoids from Hypericum perforatum show antidepressant activity in the forced swimming test. Planta Med. 2000; 66 3-6
- 4 Manach C, Williamson G, Morand C, Scalbert A, Remesy C. Bioavailability and bioefficacy of polyphenols in humans. Am J Clin Nutr. 2005; 81 230S-42S
- 5 Manach C, Donovan J L. Pharmacokinetics and metabolism of dietary flavonoids in humans. Free Radic Res. 2004; 38 771-85
- 6 Walle T. Absorption and metabolism of flavonoids. Free Radic Biol Med. 2004; 36 829-37
- 7 Scalbert A, Morand C, Manach C, Remesy C. Absorption and metabolism of polyphenols in the gut and impact on health. Biomed Pharmacother. 2002; 56 276-82
- 8 Duthie G G, Gardner P T, Kyle J AM. Plant polyphenols: are they the new magic bullet?. Proc Nutr Soc. 2003; 62 599-603
- 9 Hollman P CH, Bijsman M NCP, van Gameren Y, Cnossen E PJ, de Vries J HM, Katan M B. The sugar moiety is a major determinant of the absorption of dietary flavonoid glycosides in man. Free Radic Res. 1999; 31 569-73
- 10 Graefe E U, Witting J, Mueller S, Riethling A K, Uehleke B, Drewelow B. et al . Pharmacokinetics and bioavailability of quercetin glycosides in humans. J Clin Pharmacol. 2001; 41 492-9
- 11 Cermak R, Landgraf S, Wolffram S. The bioavailability of quercetin in pigs depends on the glycoside moiety and dietary factors. J Nutr. 2003; 133 2802-7
- 12 Zhang Q J, Yang M, Zhao Y M, Luan X H, Ke Y G. Isolation and sturcture identification of flavonol glycosides from glandless cotton seeds. Acta Pharm Sin. 2001; 36 827-31
- 13 Li Y F, Yang M, Yuan L, Zhao Y M, Luan X H, Luo Z P. Antidepressant effect of quercetin 3-O-apiosyl (1→2)-[rhamnosyl(1→6)]-glucoside in mice. Chin J Pharmacol Toxicol. 2000; 14 125-7
- 14 Guo J F, Zhao Y M, Zhao L, Zhang W Q, Zhang A J, Xu B. Simultaneous quantification of CTN986 and its deglycosylation products in rat serum using liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom. 2006; 20 1701-8
- 15 Matsumoto M, Matsukawa N, Mineo H, Chiji H, Hara H. A soluble flavonoid-glycoside, αG-rutin, is absorbed as glycosides in the isolated gastric and intestinal mucosa. Biosci Biotechnol Biochem. 2004; 68 1929-34
- 16 Wolffram S, Block M, Ader P. Quercetin-3-glucoside is transported by the glucose carrier SGLT1 across the brush border membrane of rat small intestine. J Nutr. 2002; 132 630-5
- 17 Gee J M, DuPont M S, Rhodes M J, Jhonson I T. Quercetin glucosides interact with the intestinal glucose transport pathway. Free Radic Biol Med. 1998; 25 19-25
- 18 Hidalgo I J, Hillgren K M, Grass G M, Borchardt R T. Characterization of the unstirred water layer in Caco-2 cell monolayers using a novel diffusion apparatus. Pharm Res. 1991; 8 222-7
- 19 Matsumoto M, Chiji H, Hara H. Intestinal absorption and metabolism of a soluble flavonoid, αG-rutin, in portal cannulated rats. Free Radic Res. 2005; 39 1139-46
- 20 Erlund I, Kosonen T, Alfthan G, Mäenpää J, Perttunen K, Kenraali J. et al . Pharmacokinetics of quercetin from quercetin aglycone and rutin in healthy volunteers. Eur J Clin Pharmacol. 2000; 56 545-53
- 21 Liu F, Xu Y, Rui L, Gao S, Dong H J, Guo Q X. Liquid chromatography/tandem mass spectrometry assay for the quantification of troxerutin in human plasma. Rapid Commun Mass Spectrom. 2006; 20 3522-6
- 22 Chung H J, Choi Y H, Choi H D, Jang J M, Shim H J, Yoo M. et al . Pharmacokinetics of DA-6034, an agent for inflammatory bowel disease, in rats and dogs: contribution of intestinal first-pass effect to low bioavailability in rats. Eur J Pharm Sci. 2006; 27 363-74
- 23 Ader P, Wessmann A, Wolffram S. Bioavailability and metabolism of the flavonol quercetin in the pig. Free Radic Biol Med. 2000; 28 1056-67
- 24 Carbonaro M, Grant G. Absorption of quercetin and rutin in rat smalll intestine. Ann Nutr Metab. 2005; 49 178-82
Prof. Dr. Yimin Zhao
Beijing Institute of Pharmacology and Toxicology
27 Taiping Road
Haidian District
Beijing 100850
People’s Republic of China
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