Planta Med 2010; 76(1): 70-75
DOI: 10.1055/s-0029-1185946
Pharmacology
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Increased Oral AUC of Baicalin in Streptozotocin-Induced Diabetic Rats due to the Increased Activity of Intestinal β-Glucuronidase

Li Liu1 , Yuan-Xiong Deng1 , 2 , Yan Liang1 , Xiao-Yan Pang1 , Xiao-Dong Liu1 , Yao-Wu Liu1 , Jian-Song Yang3 , Lin Xie1 , Guang-Ji Wang1
  • 1Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, P. R. China
  • 2Medical College of Hunan Normal University, Changsha, P. R. China
  • 3Simcyp Limited, Blades Enterprise Centre, Sheffield, U. K.
Further Information

Publication History

received Nov. 22, 2008 revised June 11, 2009

accepted June 16, 2009

Publication Date:
28 July 2009 (online)

Abstract

The purpose of the study was to investigate the pharmacokinetics of baicalin, a major bioactive component of Scutellariae radix, in diabetic conditions. The 4-week diabetic rats were induced by intraperitoneal administration of streptozotocin. Plasma concentrations of baicalin were measured following oral (200 mg/kg) or intravenous (12 mg/kg) administration. Everted intestinal transport, intestinal mucosal metabolism of baicalin and intestinal β-glucuronidase activity were also investigated. It was found that the diabetic condition significantly increased the exposure of baicalin following oral doses (AUC 100.77 ± 4.16 µg · h/mL in diabetic rats vs. 48.48 ± 7.94 µg · h/mL in normal rats). In contrast, the diabetic condition significantly decreased the exposure of baicalin following intravenous doses (AUC 11.20 ± 2.28 µg · h/mL in diabetic rats vs. 18.02 ± 3.45 µg · h/mL in normal rats). We also found lower apparent permeability coefficients of baicalin in the ileum of diabetic rats (8.43 × 10−6 ± 2.40 × 10−6 cm/s in diabetic rats vs. 5.21 × 10−5 ± 1.55 × 10−5 cm/s in normal rats). Further studies showed that the diabetic condition enhanced the hydrolysis of baicalin to baicalein in intestinal mucosal, accompanied by an increase of β-glucuronidase activity. All these results suggested that the higher oral exposure of baicalin in diabetic rats did not result from the decreased hepatic metabolism or increased intestinal absorption of baicalin. The enhancement of intestinal β-glucuronidase activity may partly account for the higher exposure of baicalin in diabetic rats after oral administration.

References

  • 1 Kim Y C, Lee A K, Lee J H, Lee I, Lee D C, Kim S H, Kim S G, Lee M G. Pharmacokinetics of theophylline in diabetes mellitus rat: induction of CYP1A2 and CYP2E1 on 1,3-dimethyluric acid formation.  Eur J Pharm Sci. 2005;  26 114-123
  • 2 Sindhu R K, Koo J R, Sindhu K K, Ehdaie A, Farmand F, Roverts C K. Differential regulation of hepatic cytochrome P450 monooxygenases in streptozotocin-induced diabetic rats.  Free Radic Res. 2006;  40 921-928
  • 3 Borbás T, Benkő B, Dalmadi B, Szabó I, Tihanyi K. Insulin in flavin-containing monooxygenase regulation flavin-containing monooxygenase and cytochrome P450 activities in experimental diabetes.  Eur J Pharm Sci. 2006;  28 51-58
  • 4 Carnovale C E, Marinelli R A, Garay E A R. Bile flow decrease and altered bile composition in streptozotocin-treated rats.  Biochem Pharmacol. 1986;  35 2625-2628
  • 5 Price V F, Jollow D J. Strain differences in susceptibility of normal and diabetic rats to acetaminophen hepatotoxicity.  Biochem Pharmacol. 1986;  35 687-695
  • 6 Nadai M, Yoshizumi H, Kuzuya T, Hasegawa T, Johno I, Kitazawa S. Effect of diabetes on disposition and renal handling of cefazolin in rats.  Drug Metab Dispos. 1990;  18 565-570
  • 7 Watkins III J B, Sanders R A. Diabetes mellitus-induced alternations of hepatobiliary function.  Pharmacol Rev. 1995;  47 1-23
  • 8 Kitamura K, Honda M, Yoshizaki H, Yamamoto S, Nakane H, Fukushima M, Ono K, Tokunaga T. Baicalin, an inhibitor of HIV-1 production in vitro.  Antiviral Res. 1998;  37 131-140
  • 9 Shieh D E, Liu L T, Lin C C. Antioxidant and free radical scavenging effects of baicalein, baicalin and wogonin.  Anticancer Res. 2000;  20 2861-2865
  • 10 Kubo M, Matsuda H, Tanaka M, Kimura Y, Okuda H, Higashino M, Tani T, Namba K, Arichi S. Studies on Scutellariae radix. VII. Anti-arthritic and antiinflammatory actions of methanolic extract and flavonoid components from Scutellariae radix.  Chem Pharm Bull. 1984;  32 2724-2729
  • 11 Kimura Y, Kubo M, Tani T, Arichi S, Okuda H. Studies on Scutellariae radix. IV. Effects on lipid peroxidation in rat liver.  Chem Pharm Bull. 1981;  29 2610-2617
  • 12 Liu C S, Li P. Effects of baicalin on erythrocyte aldose reductase activity and early diabetes nephropathy.  Chin J Gerontol. 2001;  21 334-335
  • 13 Liu C S. Effects of baicalin on erythrocyte aldose reductase activity and nerve conduction velocity in patients with diabetes.  Neurosci Bull. 2002;  18 555-557
  • 14 Akao T, Kawabata K, Yanagisawa E. Baicalin, the predominant flavone glucuronide of Scutellariae radix, is absorbed from the rat gastrointestinal tract as the aglycone and restored to its original form.  J Pharm Pharmacol. 2000;  52 1563-1568
  • 15 Liu T M, Jiang X H. Investigation of the absorption mechanisms of baicalin and baicalein in rats.  J Pharm Sci. 2006;  95 1326-1333
  • 16 Lai M Y, Hsiu S L, Tsai S Y, Hou Y C, Chao P D. Comparison of metabolic pharmacokinetics of baicalin and baicalein in rats.  J Pharm Pharmacol. 2003;  55 205-209
  • 17 Zhang L, Lin G, Chang Q, Zuo Z. Role of intestinal first-pass metabolism of baicalein in its absorption process.  Pharm Res. 2005;  22 1050-1058
  • 18 Suh K S, Nam Y H, Ahn Y M. Effect of Scutellariae radix extract on the high glucose-induced apoptosis in cultured vascular endothelial cells.  Biol Pharm Bull. 2003;  26 1629-1632
  • 19 Park S M, Hong S M, Sung S R, Lee J E, Kwon D Y. Extracts of Rehmanniae radix, Ginseng radix and Scutellariae radix improve glucose-stimulated insulin secretion and beta-cell proliferation through IRS2 induction.  Genes Nutr. 2008;  2 347-351
  • 20 Lenzen S. The mechanisms of alloxan- and streptozotocin-induced diabetes.  Diabetologia. 2008;  51 216-226
  • 21 Ahn C, Bae S, Bae S, Kim T, Jung Y, Kim Y, Lee M, Shin W. Pharmacokinetics of oltipraz in diabetic rats with liver cirrhosis.  Br J Pharmacol. 2009;  156 1019-1028
  • 22 Lee J H, Lee M G. Telithromycin pharmacokinetics in rat model of diabetes mellitus induced by alloxan or streptozotocin.  Pharm Res. 2008;  25 1915-1924
  • 23 Choi Y H, Lee D C, Lee I, Lee M G. Changes in metformin pharmacokinetics after intravenous and oral administration to rats with short-term and long-term diabetes induced by streptozotocin.  J Pharm Sci. 2008;  97 5363-5375
  • 24 Harris R Z, Jang G R, Tsunoda S. Dietary effects on drug metabolism and transport.  Clin Pharmacokinet. 2003;  42 1071-1088
  • 25 Kamei J, Hirano S, Miyata S, Saito A, Onodera K. Effects of first- and second-generation histamine-H1-receptor antagonists on the pentobarbital-induced loss of the righting reflex in streptozotocin-induced diabetic mice.  J Pharmacol Sci. 2005;  97 266-272
  • 26 Lu T, Song J, Huang F, Deng Y, Xie L, Wang G, Liu X. Comparative pharmacokinetics of baicalin after oral administration of pure baicalin, radix Scutellariae extract and Huang-Lian-Jie-Du-Tang to Rats.  J Ethnopharmacol. 2007;  110 412-418
  • 27 Tsai P L, Tsai T H. Pharmacokinetics of baicalin in rats and its interactions with cyclosporin A, quinidine and SKF-525A: a microdialysis study.  Planta Med. 2004;  70 1069-1074
  • 28 Xing J, Chen X Y, Zhong D F. Absorption and enterohepatic circulation of baicalin in rats.  Life Sci. 2005;  78 140-146
  • 29 Sha X, Fang X. Transport characteristics of 9-nitrocamptothecin in the human intestinal cell line Caco-2 and everted gut sacs.  Int J Pharm. 2004;  272 161-171
  • 30 Hou Y C, Hsiu S L, Ching H, Lin Y T, Tsai S Y, Wen K C, Chao P D. Profound difference of metabolic pharmacokinetics between pure glycyrrhizin and glycyrrhizin in licorice decoction.  Life Sci. 2005;  76 1167-1176
  • 31 Fishman W H, Kato K, Anstiss C L, Green S. Human serum beta-glucuronidase; its measurement and some of its properties.  Clin Chim Acta. 1967;  15 435-447
  • 32 Jin L Z, Ho Y W, Abdullah N, Jalaludin S. Digestive and bacterial enzyme activities in broilers fed diets supplemented with Lactobacillus cultures.  Poult Sci. 2000;  79 886-891
  • 33 Mircheff A K, Wright E M. Analytical isolation of plasma membranes of intestinal epithelial cells: identification of Na, K-ATPase rich membranes and the distribution of enzyme activities.  J Membrane Biol. 1976;  28 309-333
  • 34 Zoubi S A, Mayhew T M, Sparrow R A. The small intestine in experimental diabetes: cellular adaptation in crypts and villi at different longitudinal sites.  Virchows Arch. 1995;  426 501-507
  • 35 Rozanova G N, Voevedin D A, Stenina M A, Kushnareva M V. Pathogenetic role of dysbacteriosis in the development of complications of type 1 diabetes mellitus in children.  Bull Exp Biol Med. 2002;  133 164-166
  • 36 Akao T, Hanada M, Sakashita Y, Sato K, Morita M, Imanaka T. Efflux of baicalin, a flavone glucuronide of Scutellariae radix, on Caco-2 cells through multidrug resistance-associated protein 2.  J Pharm Pharmacol. 2007;  59 87-93
  • 37 Carnovale C E, Catania V A, Monti J A, Carrillo M C. Differential effects of blood insulin levels on microsomal enzyme activities from hepatic and extrahepatic tissues of male rats.  Can J Physiol Pharmacol. 1992;  70 727-731
  • 38 Kameyama N, Arisawa S, Ueyama J, Kagota S, Shinozuka K, Hattori A, Tatsumi Y, Hayashi H, Takagi K, Wakusawa S. Increase in P-glycoprotein accompanied by activation of protein kinase Calpha and NF-kappaB p 65 in the livers of rats with streptozotocin-induced diabetes.  Biochim Biophys Acta. 2008;  1782 355-360
  • 39 Aleksunes L M, Sawant S P, Dnyanmote A V, Mehendale H M, Manautou J E, Nowicki M T. Renal and hepatic transporter expression in type 2 diabetic rats.  Drug Metab Lett. 2008;  2 11-17

Prof. Xiao-Dong Liu

Key Laboratory of Drug Metabolism and Pharmacokinetics
China Pharmaceutical University

210009 Nanjing

People's Republic of China

Phone: + 86 25 83 27 10 06

Fax: + 86 25 85 30 67 50

Email: xdliu@cpu.edu.cn

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