Oral characteristics of bergenin and the effect of absorption enhancers in situ, in vitro and in vivo

Abstract

The purpose of this study was to explore the absorption characteristics of bergenin (CAS 477-90-7) and to improve its bioavailability by modulation of the gastrointestinal (GI) absorption using two enhancers (borneol and Poloxamer 188, resp. F68) based on in situ absorption model, in vitro Caco-2 monolayer and in vivo pharmacokinetics studies and comparing the results obtained. The effect of borneol and F68 on drug absorption was quantified at two concentration levels (1 or 4 mg/ml). The observations from in situ and in vitro model indicated that the oral absorption of bergenin is limited and passive diffusion could be the main manner. After oral administration alone (60 mg/kg), a biphasic characteristic was observed. AUC_0→∞ was only 1.95 ± 0.29 μg × h/ml and C_max was 0.44 ±0.11 μg/ml. From the results of in situ experiments, both of the enhancers were able to increase the absorption percentage of bergenin. Significantly increased (P < 0.05) apparent permeability was observed in Caco-2 cell monolayer. The oral bioavailability of bergenin in rats was improved in the presence of borneol or F68. AUC_0→∞ increased significantly (P < 0.05) to 8.61 ± 3.74 and 3.41 ± 1.17 μg × h/ml, which were 4.42 and 1.75-fold higher with borneol and F68 than that of the control group, respectively. The enhanced bioavailability suggests that borneol and F68 could promote the absorption of bergenin in the GI tract.

Key words

Absorption enhancers - Bergenin, bioavailability, oral absorption, pharmacokinetics - Caco-2 cell monolayer

• References

• 1 Nazir N, Koul S, Qurishi MA, Taneja SC, Ahmad SF, Bani S et al Immunomodulatory effect of bergenin and norber-genin against adjuvant-induced arthritis-a flow cytometric study. J Ethnopharmacol. 2007; 112: 401-5
• 2 Ye YP, Sun HX, Pan YJ.. Bergenin monohydrate from the rhizomae of Astilbe chinensis. Acta crystallogr C. 2004; 60: 397-8
• 3 Chinese Pharmacopoeia Commission. The Pharmacopoeia of the People's Republic of China. 2005; part I: 278.
• 4 Hack SK, Hwa KL, Myeon WC, Young CK.. Antihepatotoxic activity of bergenin, the major constituent of Mallotus ja-ponicus, on carbon tetrachloride-intoxicated hepatocytes. J Ethnopharmacol. 2000; 69: 79-83
• 5 Wang G, Ma J. Overview of Recent Progresson bergenin. Anhui Zhong Yi Xue Yuan Xue Bao. 2002; 21: 59-62
• 6 Lim HK, Kim HS, Choi HS, Choi J, Kim SH, Chang MJ. Effects of bergenin the major constituent of Mallotus japonicus against D-galactosamine-induced hepatotoxicity in rats. Pharmacology. 2001; 63: 71-5
• 7 Piacente S, Pizza C, Tommasi N, Mahmood N.. Constituents of Ardisia japonica and their in vitro anti-ΗIV activity. J Nat Prod. 1996; 59: 565-9
• 8 Takahashi H, Kosaka M, Watanabe Y, Nakade K, Fukuyama Y.. Synthesis and neuroprotective activity of bergenin derivatives with antioxidant activity. Bioorg Med Chem. 2003; 11: 1781-8
• 9 Jiangsu New Medical College. Traditional Medicine. Shanghai: People press; 1999; p. 2359.
• 10 Wang G, Liu JK, Ma BJ, inventors. Chen Z, assignee. The acetylate of bergenin and its application. P. R. China patent 200510010970.0. 2006.
• 11 Cyril R, Olivier RM.. Synthesis of bergenin-related natural products by way of an intramolecular C-glycosylation reaction. Tetrahedron Asymmetr. 2000; 11: 409-12
• 12 Li XD, Lu SL, He B, inventors. Liu AN, assignee. The preparation of bergenin compositae pills. P. R. China patent 200410040660.9. 2005.
• 13 Li J, inventor. The preparation of bergenin compositae soft capsules. P. R. China patent 200410078846.3. 2005.
• 14 Guan JY, Sun DJ, Wu GL.. The study of bergenin's inclusion complex. Zhong Cheng Yao. 1991; 13: 4-5
• 15 Shinya T, Takeo K, Takahiro M, Yuji H, Hiroyuki Y.. Enhancement of intestinal absorption of poorly absorbed hy-drophilic compounds by simultaneous use of mucolytic agent and non-ionic surfactant. Eur J Pharm Biopharm. 2006; 62: 52-58
• 16 Aungst BJ.. Intestinal permeation enhancers. / Pharm Sci. 2000; 89: 429-42
• 17 Feng L, Jiang XH.. Absorption profiles of sanchinoside Rl and ginsenoside Rgl in the rat intestine. Eur J Drug Metab Pharmacokinet. 2005; 30: 26-8
• 18 Bermejo MV, Pérez-Varona AT, Segura-Bono MJ, Martin-Villodre A, Pla-Delfma JM, Garrigues TM.. Compared effects of synthetic and natural bile acid surfactants on xenobiotic absorption I. Studies with polysorbate and taurocholate in rat colon. Int JPharm. 1991; 69: 221-31
• 19 Teodoro Z, Maria JC, Ricardo NM, Consuelo G, Luis G, Ana P.. Assessment and modulation of acamprosate intestinal absorption: comparative studies using in situ, in vitro (CACO-2 cell monolayers) and in vivo models. Eur J Pharm Sci. 2004; 22: 347-56
• 20 Schurgers N, Bijdendijk J, Tukker J, Crommelin D.. Comparison of four experimental techniques for studying drug absorption kinetics in the anesthetized rat in situ. / Pharm Sei. 1986; 75: 117-9
• 21 Sawamoto T, Haruta S, Kurosaki Y, Higaki K, Kimura T.. Prediction of the plasma concentration profiles of orally administered drugs in rats on the basis of gastrointestinal transit kinetics and absorbability. / Pharm Pharmacol. 1997; 49: 450-7
• 22 Xuan Q, Dan Z, Zhi RZ, Yuan H.. Determination of bergenin in rat plasma by high-performance liquid chromatography. Pharmazie. 2007; 62: 323-6
• 23 Ren J, Jiang XH, Li C, Li K, Chen Z, Ma G.. Absorptive profile of chlorogenic acid in rats. Pharmazie. 2007; 62: 689-92
• 24 Tsuji A, Miyamoto E, Kagami I, Sakaguchi H, Yamana T.. GI absorption of beta-lactam antibiotics I: kinetic assessment of competing absorption and degradation in GI tract. J Pharm Sci. 1978; 67: 1701-4
• 25 Pratima S, Gupta RC.. In situ absorption and protein binding characteristics of CDRI-85/92, an antiulcer pharmacophore. Int J Pharm. 2003; 257: 97-102
• 26 Barbra H, Stewart O, Helen C, Nancy J.. Discrimination between drug candidates using models for evaluation of intestinal absorption. Adv Drug Deliver Rev. 1997; 23: 27-25
• 27 Dan Z, Xuan Q, Zhi RZ, Yuan H.. Physicochemical properties of bergenin. Pharmazie. 2008; 63: 366-71
• 28 Sibylle N, Anna-Lena U, Ismael Z, Per A.. pH-Dependent passive and active transport of acidic drugs across Caco-2 cell monolayers. Eur J Pharm Sei. 2005; 25: 211-20
• 29 Lipka E, Amidon GL.. Setting bioequivalence requirements for drug development based on preclinical data: optimizing oral drug delivery systems. / Control Release. 1999; 62: 41-9
• 30 Shrutidevi A, Ramesh P.. Implication of biopharmaceutics and pharmacokinetics of rifampicin in variable bioavailability from solid oral dosage forms. Biopharm Drug Dispos. 2005; 26: 321-34
• 31 Fan ZL, Jian F, Qiao YC, Wen JZ, Yu JJ.. Delivery of ¹²⁵I-co-brotoxin after intranasal administration to the brain: A mi-crodialysis study in freely moving rats. Int J Pharm. 2007; 328: 161-7
• 32 Yong CS, Yang CH, Rhee JD, Lee BJ, Kim DC, Kim DD et al Enhanced rectal bioavailability of Ibuprofen in rats by po-loxamer 188 and menthol. Int J Pharm. 2004; 269: 169-76
• 33 Hui BX, Kai XH, Yu SZ, Qiu HG, Qing ZW, Wei QT et al Hypoglycaemic effect of a novel insulin buccal formulation on rabbits. Pharmacol Res. 2002; 46: 459-67
• 34 Zhu JP, Wang ZR, Wu NX.. [Enhanced percutaneous penetration with borneol]. Zhongguo Yao Xue Za Zhi. 1999; 34: 104-6
• 35 Wang H, Xu WR, Wang ZR.. [Effect of 1-menthol and synthetic borneol on enhanced percutaneous penetration]. Zhong Cao Yao. 1997; 28: 93-95
• 36 Chen YM, Wang NS.. Effect of borneol on P-glycoprotein. Tradit Chin Drug Res Clin Pharmacol. 2003; 14: 96-99
• 37 Chen YM, Wang NS.. [Effect of borneol on the intercellular tight junction and pinocytosis vesicles in vitro blood-brain barrier model]. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004; 24: 632-4
• 38 Kotzé AF, Thanou MM, Lueßen HL, Boer AG, Verhoef JC, Junginger HE.. Effect of the degree of quaternization of N-trimethyl chitosan chloride on the permeability of intestinal epithelial cells (Caco-2). Eur J Pharm Biopharm. 1999; 47: 269-74
• 39 Belsito D, Bickers D, Bruze M, Calow P, Greim H, Hanifin JM et al A toxicologic and dermatologie assessment of cyclic and non-cyclic terpene alcohols when used as fragrance ingredients. Food Chem Toxicol. 2008; 46: S1-S71
• 40 Xiao YY, Ping QN, Chen ZP.. The enhancing effect of synthetical borneol on the absorption of tetramethylpyra-zine phosphate in mouse. Int J Pharm. 2007; 337: 74-9
• 41 Li XR, Xu W, Feng YF.. [Effects of borneol or menthol on nitrendipine absorption in rabbit]. Zhongguo Yi Yuan Yao Xue Za Zhi. 2001; 21: 264-6
• 42 Lin ZZ, Yao MC, Lan MX, Liu PJ, Zhong GP, Pi RB.. [Effect of borbeol on distribution of sodium ferulate in plasma and in brain regions of mice]. Zhong Cao Yao. 2000; 39: 551-6
• 43 Edward LL, Steven CS.. In vitro models for selection of development candidates: Permeability studies to define mechanism of absorption enhancement. Adv Drug Deliv Rev. 1997; 23: 163-83
• 44 Alamdar H, John JA, Mansoor AK, Fakhrul A.. Absorption enhancers in pulmonary protein delivery. / Control Release. 2004; 94: 15-24
• 45 Schipper NG, Varum KM, Stenberg P, Ocklind G, Lenner-näs H, Artursson P.. Chitosans as absorption enhancers of poorly absorbable drugs: Influence of mucus on absorption enhancement. Eur J Pharm. 1999; 8: 335-43