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Planta Medica International Open 2017; 4(02): e66-e73
DOI: 10.1055/s-0043-114669
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

Multiple Oral Dosing Pharmacokinetics of Standardized Extract of Centella asiatica ECa 233 and Its Inductive Effect on Efflux Transporters in Rats

Tosapol Anukunwithaya
1   Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
,
Mayuree H. Tantisira
2   Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
3   Faculty of Pharmaceutical Sciences, Burapha University, Chonburi, Thailand
,
Tsutomu Shimada
4   Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, Kanazawa University, Takara-machi, Kanazawa, Japan
5   Department of Hospital Pharmacy, University Hospital, Kanazawa University, Takara-machi, Kanazawa, Japan
,
Yoshimichi Sai
4   Department of Clinical Pharmacokinetics, Graduate School of Medical Sciences, Kanazawa University, Takara-machi, Kanazawa, Japan
5   Department of Hospital Pharmacy, University Hospital, Kanazawa University, Takara-machi, Kanazawa, Japan
,
Phisit Khemawoot
1   Department of Pharmacology and Physiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
2   Chulalongkorn University Drug and Health Products Innovation Promotion Center, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok, Thailand
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Weitere Informationen

Publikationsverlauf

received 14. März 2017
revised 15. Mai 2017

accepted 06. Juni 2017

Publikationsdatum:
28. August 2017 (online)

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Abstract

ECa 233 is a standardized extract of Centella asiatica, characterized as a white powder containing triterpenoid glycosides not less than 80% with a ratio of madecassoside to asiaticoside of 1.5±0.5:1. Although pharmacological and toxicological profiles of ECa 233 have been successively reported, the pharmacokinetic data needed for further therapeutic development are not fully elucidated. This study aimed to investigate the pharmacokinetics of multiple oral dosing of ECa 233 at 100 mg/kg/day for 7 days in rats. Plasma, tissues, urine, and feces were collected from 0 to 24 h after dosing on days 1 and 7. The concentrations of asiaticoside, madecassoside, asiatic acid, and madecassic acid were simultaneously analyzed by liquid chromatography-tandem mass spectrometry. No significant change was observed in physical and blood biochemical parameters of the animals treated with ECa 233 for 7 days. The maximum plasma concentration and area under the curve at day 7 of madecassoside and asiaticoside decreased by 70–80% from day 1. However, both triterpenoid glycosides were extensively distributed and accumulated, resulting in significantly higher concentrations at pharmacologically relevant organs. Madecasssic acid and asiatic acid are major metabolites mainly found in and excreted via feces. Moreover, multiple dosing of ECa 233 increased mRNA expression of Abcb1a and Abcc2 in the small intestine by approximately 2- to 3-fold. This is the first study to identify an inductive effect of a standardized extract of C. asiatica after multiple oral dosing in rats. Potential drug-herb interactions when ECa 233 is coadministered with Abcb1a and Abcc2 substrates calls for further investigations.

Key words

Centella asiatica - Apiaceae - ECa 233 - madecassoside - asiaticoside - pharmacokinetics

Supporting Information

    1D and 2D NMR spectra of 1a/1b, 2a/2b and 3a/3b are available online at http://www.thieme-connect.de/products.
  • Supporting Information
 

  • References

  • 1 Jamil SS, Nizami Q, Salam M. Centella asiatica (Linn.) Urban: a review. Indian J Nat Prod Res 2007; 6: 158-170
    PubMedGoogle Scholar
  • 2 Krittapun W. Usefulness of Herbs. Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University; 1996
    PubMed
  • 3 Bown D. Encyclopedia of herbs and their uses (Herb Society of America). New York: Dorling Kindersley; 1995
    Google Scholar
  • 4 Maquart FX, Chastang F, Simeon A, Birembaut P, Gillery P, Wegrowski Y. Triterpenes from Centella asiatica stimulate extracellular matrix accumulation in rat experimental wounds. Eur J Dermatol 1999; 9: 289-296
    PubMedGoogle Scholar
  • 5 Shukla A, Rasik AM, Jain GK, Shankar R, Kulshrestha DK, Dhawan BN. In vitro and in vivo wound healing activity of asiaticoside isolated from Centella asiatica. J Ethnopharmacol 1999; 65: 1-11
    CrossrefPubMedGoogle Scholar
  • 6 Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimer’s disease in rats. Clin Exp Pharmacol Physiol 2003; 30: 336-342
    CrossrefPubMedGoogle Scholar
  • 7 Cheng CL, Koo MWL. Effects of Centella asiatica on ethanol induced gastric mucosal lesions in rats. Life Sci 2000; 67: 2647-2653
    CrossrefPubMedGoogle Scholar
  • 8 Cesarone MR, Belcaro G, De Sanctis MT, Incandela L, Cacchio M, Bavera P, Ippolito E, Bucci M, Griffin M, Geroulakos G, Dugall M, Buccella S, Kleyweght S, Cacchio M. Effects of the total triterpenic fraction of Centella asiatica in venous hypertensive microangiopathy: a prospective, placebo-controlled, randomized trial. Angiology 2001; 52: S15-S18
    CrossrefPubMedGoogle Scholar
  • 9 Punturee K, Wild CP, Vinitketkumneun U. Thai medicinal plants modulate nitric oxide and tumor necrosis factor-α in J774.2 mouse macrophages. J Ethnopharmacol 2004; 95: 183-189
    CrossrefPubMedGoogle Scholar
  • 10 James JT, Dubery IA. Pentacyclic triterpenoids from the medicinal herb, Centella asiatica (L.) Urban. Molecules 2009; 14: 3922-3941
    CrossrefPubMedGoogle Scholar
  • 11 Guo JS, Cheng CL, Koo MWL. Inhibitory effects of Centella asiatica water extract and asiaticoside on inducible nitric oxide synthase during gastric ulcer healing in rats. Planta Med 2004; 70: 1150-1154
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 12 Saifah E, Suttisri R, Patarapanich C, Laungchonlatan S, Tantisira MH, Tantisira B. Preparation methods of colorless mixture between madecassoside and asiaticoside from Centella asiatica. In: Department of Intellectual Property MoC . ed. C07H 1/00 ed. Bangkok, Thailand: Chulalongkorn University; 2009.
    Google Scholar
  • 13 Tantisira MH. Bioactive standardized extract of Centella asiatica (ECa 233). In: The Eighth NRCT-JSPS Joint Seminar. Bangkok, Thailand: Chulalongkorn University Printing Press; 2009. 25
    Google Scholar
  • 14 Wanasuntronwong A, Tantisira MH, Tantisira B, Watanabe H. Anxiolytic effects of standardized extract of Centella asiatica (ECa 233) after chronic immobilization stress in mice. J Ethnopharmacol 2012; 143: 579-585
    CrossrefPubMedGoogle Scholar
  • 15 Wannarat K, Tantisira MH, Tantisira B. Wound healing effects of a standardized extract of Centella asiatica ECa 233 on burn wound in rats. Thai J Pharmacol 2009; 31: 120-123
    PubMedGoogle Scholar
  • 16 Ruengprasertkit C, Hongprasong N, Tantisira B, Tantisira MH. Preliminary study of effects of a standardized extract of Centella asiatica ECa 233 on minor aphthous ulcers. Chulalongkorn Univ Dent J 2010; 33: 131-142
    PubMedGoogle Scholar
  • 17 Kam-eg A, Tantisira B, Tantisira MH. Preliminary study on effects of a standardized extract of Centella asiatica, ECa 233, on deficit of learning and memory induced by an intracerebroventricular injection of β-amyloid peptide in mice. Thai J Pharmacol 2009; 31: 79-82
    PubMedGoogle Scholar
  • 18 Wanakhachornkrai O, Pongrakhananon V, Chunhacha P, Wanasuntronwong A, Vattanajun A, Tantisira B, Chanvorachote P, Tantisira M. Neuritogenic effect of standardized extract of Centella asiatica ECa 233 on human neuroblastoma cells. BMC Complement Altern Med 2013; 13: 204
    CrossrefPubMedGoogle Scholar
  • 19 Chivapat S, Chavalittumrong P, Tantisira MH. Acute and sub-chronic toxicity studies of a standardized extract of Centella asiatica ECa 233. Thai J Pharm Sci 2011; 35: 55-64
    PubMedGoogle Scholar
  • 20 Anukunwithaya T, Tantisira MH, Tantisira B, Khemawoot P. Pharmacokinetics of a standardized extract of Centella asiatica ECa 233 in rats. Planta Med 2017; 83: 710-717
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 21 Hengjumrut P, Anukunwithaya T, Tantisira MH, Tantisira B, Khemawoot P. Comparative pharmacokinetics between madecassoside and asiaticoside presented in a standardised extract of Centella asiatica, ECa 233 and their respective pure compound given separately in rats. Xenobiotica advance online publication 8 January 2017 DOI: 10.1080/00498254.2016.1273562.
    CrossrefPubMedGoogle Scholar
  • 22 Tirona RG, Kim RB. Nuclear receptors and drug-drug interactions with prescription and herbal medicines. In: Xie W. editor. Nuclear receptors in drug metabolism. Hoboken, New Jersey: John Wiley & Sons, Inc; 2008: 211-239
    CrossrefGoogle Scholar
  • 23 Oga E, Sekine S, Shitara Y, Horie T. Pharmacokinetic herb-drug interactions: insight into mechanisms and consequences. Eur J Drug Metab Pharmacokinet 2016; 41: 93-108
    CrossrefPubMedGoogle Scholar
  • 24 Leng DD, Han WJ, Rui Y, Dai Y, Xia YF. In vivo disposition and metabolism of madecassoside, a major bioactive constituent in Centella asiatica (L.) Urb. J Ethnopharmacol 2013; 150: 601-608
    CrossrefPubMedGoogle Scholar
  • 25 Kulthong K, Tantisira MH, Niwattisaiwong N, Apipalakul K, Chevapat S, Lawanprasert S. Effects of the standard extract of Centella asiatica (ECa 233) on rat hepatic cytochrome P450. Thai J Pharm Sci 2009; 33: 91-100
    PubMedGoogle Scholar
  • 26 Krishnamurthy RG, Senut MC, Zemke D, Min J, Frenkel MB, Greenberg EJ, Yu SW, Ahn N, Goudreau J, Kassab M, Panickar KS, Majid A. Asiatic acid, a pentacyclic triterpene from Centella asiatica, is neuroprotective in a mouse model of focal cerebral ischemia. J Neurosci Res 2009; 87: 2541-2550
    CrossrefPubMedGoogle Scholar
  • 27 Rush WR, Murray GR, Graham DJM. The comparative steady-state bioavailability of the active ingredients of madecassol. Eur J Drug Metab Pharmacokinet 1993; 18: 323-326
    CrossrefPubMedGoogle Scholar