Planta Med 2012; 78(7): 692-697
DOI: 10.1055/s-0031-1298368
Pharmacokinetic Investigations
Original Papers
© Georg Thieme Verlag KG Stuttgart · New York

Intestinal Transport of Pure Diester-type Alkaloids from an Aconite Extract across the Caco-2 Cell Monolayer Model

Na Li1 , 2 , Rong Tsao3 , Zhigang Sui2 , Jingwei Ma1 , Zhiqiang Liu4 , Zhongying Liu1
  • 1College of Pharmacy, Jilin University, Changchun, China
  • 2Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
  • 3Guelph Food Research Centre, Agriculture and Agri-Food Canada, Guelph, Ontario, Canada
  • 4Changchun Center of Mass Spectrometry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China
Further Information

Publication History

received October 11, 2011 revised February 10, 2012

accepted February 16, 2012

Publication Date:
12 March 2012 (online)

Abstract

Aconitine (AC), mesaconitine (MA), and hypaconitine (HA) are the active alkaloids identified in aconite tuber, an important traditional Chinese medicine. The study is aimed to investigate their intestinal transport profiles and potential interaction during the intestinal absorption using the Caco-2 cell monolayer model. All three alkaloids had good permeability with P app values greater than 1 × 10−6 cm · s−1. However, AC, MA, and HA in a mixture and as an extract, in both cases with the same content of alkaloids, showed higher transport efficiency in the apical to basolateral, and lower transport efficiency in the basolateral to apical directions. Digoxin, as a P-glycoprotein (P-gp) substrate, was substantially effluxed in the basolateral to apical direction but inhibited by the three alkaloids. Furthermore, the backwards transport of MA and HA was inhibited by the P-gp inhibitor verapamil. These observations indicated that the three alkaloids may not only be P-gp inhibitors but also its substrates; they interact with each other and can potentially enhance their own bioavailability when taken concomitantly.

Supporting Information

References

  • 1 Singhuber J, Zhu M, Prinz S, Brigitte K. Aconitum in traditional Chinese medicine: a valuable drug or an unpredictable risk?.  J Ethnopharmacol. 2009;  126 18-30
  • 2 Kaneko R, Hattori S, Furuta S, Hamajima M, Hirata Y, Watanabe K, Seno H, Ishii A. Sensitive analysis of aconitine, hypaconitine, mesaconitine and jesaconitine in human body fluids and Aconitum tubers by LC/ESI-TOF-MS.  J Mass Spectrom. 2006;  41 810-814
  • 3 Ameri A. The effects of Aconitum alkaloids on the central nervous system.  Prog Neurobiol. 1998;  56 211-235
  • 4 Turabekova M A, Rasulev B F, Dzhakhangirov F N, Salikhov S I. Aconitum and Delphinium alkaloids “Drug-likeness” descriptors related to toxic mode of action.  Environ Toxicol Pharmacol. 2008;  25 310-320
  • 5 Tang L, Ye L, Lv C, Zheng Z J, Gong Y, Liu Z Q. Involvement of CYP3A4/5 and CYP2D6 in the metabolism of aconitine using human liver microsomes and recombinant CYP450 enzymes.  Toxicol Lett. 2011;  202 47-54
  • 6 Zhang Q L, Hu J H, Zhu Q G, Li F Q, Liu J Y, Wang D. Development of a novel HPLC-MS/MS method for the determination of aconitine and its application to in vitro and rat microdialysis samples.  Biomed Chromatogr. 2009;  23 692-699
  • 7 Kaneko R, Hattori S, Furuta S, Hamajima M, Hirata Y, Watanabe K, Seno H, Ishii A. Sensitive analysis of aconitine, hypaconitine, mesaconitine and jesaconitine in human body fluids and Aconitum tubers by LC/ESI-TOF-MS.  J Mass Spectrom. 2006;  41 810-814
  • 8 Chan T Y K. Aconite poisoning.  Clin Toxicol. 2009;  47 279-285
  • 9 Chen L, Yang J, Davey A K, Chen Y X, Wang J P, Liu X Q. Effects of diammonium glycyrrhizinate on the pharmacokinetics of aconitine in rats and the potential mechanism.  Xenobiotica. 2009;  39 955-963
  • 10 He L P, Di B, Du Y X, Yan F, Su M X, Liu H Q, You L J. Development and validation of a high-performance liquid chromatography-tandem mass spectrometry method for the rapid simultaneous quantification of aconitine, mesaconitine, and hypaconitine in rat plasma after oral administration of sini decoction.  J Anal Toxicol. 2009;  33 588-594
  • 11 Hattori H, Hirata Y, Hamajima M, Kaneko R, Ito K, Ishii A, Suzuki O, Seno H. Simultaneous analysis of aconitine, mesaconitine, hypaconitine, and jesaconitine in whole blood by LC-MS-MS using a new polymer column.  Forensic Toxicol. 2009;  27 7-11
  • 12 Tazawa T, Zhao H Q, Li Y, Meselhy M R, Nakamura N, Akao T, Hattori M. A new enzyme immunoassay for aconitine and its application to quantitative determination of aconitine levels in plasma.  Biol Pharm Bull. 2003;  26 1289-1294
  • 13 Wang Z H, Guo D, He Y, Hu C H, Zhang J Z. Quantitative determination of Aconitum alkaloids in blood and urine samples by high-performance liquid chromatography.  Phytochem Anal. 2004;  15 16-20
  • 14 Wang Z H, Wen J, Xing J B, He Y. Quantitative determination of diterpenoid alkaloids in four species of Aconitum by HPLC.  J Pharm Biomed. 2006;  40 1031-1034
  • 15 Yang X W, Huang X, Ma L A, Wu Q, Xu W. The intestinal permeability of neolignans from the seeds of Myristica fragrans in the Caco-2 cell monolayer model.  Planta Med. 2010;  76 1587-1591
  • 16 Jiang S G, Zu Y G, Zhang Y, Fu Y J, Wang Z, Wang J T. Transport of a hydrophilic paclitaxel derivative, 7-xylosyl-10-deacetylpaclitaxel, by human intestinal epithelial Caco-2 cells.  Planta Med. 2010;  76 1592-1595
  • 17 Zhang J W, Zhou F, Wu X L, Gu Y, Ai H, Zheng Y T, Li Y N, Zhang X X, Hao G, Sun J G, Peng Y, Wang G J. 20(S)-Ginsenoside Rh2 noncompetitively inhibits P-glycoprotein in vitro and in vivo: a case for herb-drug interactions.  Drug Metab Dispos. 2010;  38 2179-2187
  • 18 Liu W L, Liu Z Q, Song F R, Liu S Y. Specific conversion of diester-diterpenoid Aconitum alkaloids components into hydrolysis monoester-diterpenoid alkaloids components and lipo-alkaloids compounds.  Chem J Chin Univ. 2011;  32 717-720
  • 19 Artursson P, Karlsson J. Correlation between oral drug absorption in humans and apparent drug permeability coefficients in human intestinal epithelial (Caco-2) cells.  Biochem Biophys Res Commun. 1991;  175 880-885
  • 20 Yoshida N, Takagi A, Kitazawa H, Kawakami J, Adachi I. Inhibition of P-glycoprotein-mediated transport by extracts of and monoterpenoids contained in Zanthoxyli Fructus.  Toxicol Appl Pharmacol. 2005;  209 167-173
  • 21 De Castro W V, Mertens-Talcott S, Derendorf H, Butterweck V. Grapefruit juice-drug interactions: Grapefruit juice and its components inhibit P-glycoprotein (ABCB1) mediated transport of talinolol in Caco-2 cells.  J Pharm Sci. 2007;  96 2808-2817
  • 22 Hansen T S, Nilsen O G. Echinacea purpurea and P-glycoprotein drug transport in Caco-2 Cells.  Phytother Res. 2008;  23 86-91
  • 23 Huang M, du Plessis J, du Preez J, Hamman J, Viljoen A. Transport of aspalathin, a Rooibos tea flavonoid, across the skin and intestinal epithelium.  Phytother Res. 2008;  22 699-704
  • 24 Keogh J P, Kunta J R. Development, validation and utility of an in vitro technique for assessment of potential clinical drug-drug interactions involving P-glycoprotein.  Eur J Pharm Sci. 2006;  27 543-554
  • 25 Liu Z Q, Jiang Z H, Liu L, Hu M. Mechanisms responsible for poor oral bioavailability of paeoniflorin: role of intestinal disposition and interactions with sinomenine.  Pharm Res. 2008;  23 2768-2780
  • 26 Nahrstedt A, Butterweck V. Lessons learned from herbal medicinal products: the example of St. John's Wort.  J Nat Prod. 2010;  73 1015-1021

Dr. Zhongying Liu

College of Pharmacy
Jilin University

1266 Fujin Road

Changchun 130021

China

Phone: +86 431 85 61 97 04

Fax: +86 431 85 26 22 36

Email: liuzy@jlu.edu.cn