Pharmacokinetics of a Standardized Extract of Centella asiatica ECa 233 in Rats

Abstract

ECa 233, a standardized extract of Centella asiatica, has been found to exhibit various positive neurological effects and to have a good safety profile. The present study aimed to explore the disposition kinetics of ECa 233, containing madecassoside (53.1 %) and asiaticoside (32.3 %), in rats. The extract was intravenously or orally administered at doses from 50 to 200 mg/kg. Plasma, tissues, urine, and feces were collected at time points from 0 to 48 h after dosing. The levels of madecassoside and asiaticoside, as well as their postulated triterpenic metabolites, madecassic acid and asiatic acid, in biological samples, were simultaneously measured by liquid chromatography-tandem mass spectrometry. The results showed that all animals had a good tolerability for ECa 233, whereas madecassic and asiatic acids were found in negligible amounts after pharmacokinetic assessment. Madecassoside and asiaticoside demonstrated rather similar absorption and tissue distribution profiles. They were rapidly absorbed, reaching maximum levels within 5–15 min after oral administration, but they had poor oral bioavailability, less than 1 %. Both triterpenoids were extensively distributed in the brain, stomach, and skin within 1 h and remained there for at least 4 h after dosing. Madecassoside and asiaticoside in ECa 233 were mainly excreted as an unchanged form after being injected, and exclusively as triterpenic acid metabolites in feces after oral administration. The pharmacokinetic results obtained could provide some guidance for an appropriate dosing regimen of ECa 233 in future studies. This study also provided the first evidence demonstrating the presence of madecassoside and asiaticoside in their target tissues.

Key words

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

• References

• 1 Jamil SS, Nizami Q, Salam M. Centella asiatica (Linn.) Urban: a review. Indian J Nat Prod Resour 2007; 6: 158-170
• 2 Krittapun W. Usefulness of Herbs. Salaya, Thailand: Department of Pharmacognosy, Faculty of Pharmacy, Mahidol University; 1996
• 3 Bown D. The Herb Society of America. Encyclopedia of Herbs and their Uses. New York: Dorling Kindersley; 1995
• 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
• 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
• 6 Veerendra Kumar MH, Gupta YK. Effect of Centella asiatica on cognition and oxidative stress in an intracerebroventricular streptozotocin model of Alzheimerʼs disease in rats. Clin Exp Pharmacol Physiol 2003; 30: 336-342
• 7 Cheng CL, Koo MWL. Effects of Centella asiatica on ethanol induced gastric mucosal lesions in rats. Life Sci 2000; 67: 2647-2653
• 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. Effects of the total triterpenic fraction of Centella asiatica in venous hypertensive microangiopathy: a prospective, placebo-controlled, randomized trial. Angiology 2001; 52 (Suppl. 02) S15-S18
• 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
• 10 James J, Dubery I. Pentacyclic triterpenoids from the medicinal herb, Centella asiatica (L.) Urban. Molecules 2009; 14: 3922-3941
• 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
• 12 Bossé JP, Papillon J, Frenette G, Dansereau J, Cadotte M, Le Lorier J. Clinical study of a new antikeloid agent. Ann Plast Surg 1979; 3: 13-21
• 13 Grimaldi R, De Ponti F, DʼAngelo L, Caravaggi M, Guidi G, Lecchini S, Frigo GM, Crema A. Pharmacokinetics of the total triterpenic fraction of Centella asiatica after single and multiple administrations to healthy volunteers. A new assay for asiatic acid. J Ethnopharmacol 1990; 28: 235-241
• 14 Tantisira MH. Bioactive standardized Extract of Centella asiatica (ECa 233). Proceeding of the 8th NRCT-JSPS Joint Seminar, Bangkok, Thailand. Bangkok, Thailand: Chulalongkorn University Printing Press; 2009: 25
• 15 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
• 16 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
• 17 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. CU Dent J 2010; 33: 131-142
• 18 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
• 19 Tantisira MH, Tantisira B, Patarapanich C, Suttisri R, Luangcholatan S, Mingmalailak S, Wanasuntronwong A, Saifah E. Effects of standardized extract of Centella asiatica ECa 233 on learning and memory impairment induced by transient bilateral common carotid artery occlusion in mice. Thai J Pharmacol 2010; 32: 22-23
• 20 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
• 21 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
• 22 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
• 23 Han WJ, Xia YF, Dai Y. Development and validation of high-performance liquid chromatography/electrospray ionization mass spectrometry for assay of madecassoside in rat plasma and its application to pharmacokinetic study. Biomed Chromatogr 2012; 26: 26-32
• 24 Saifah E, Suttisri R, Patarapanich C, Laungchonlatan S, Tantisira MH, Tantisira B. Preparation methods of colorless mixture between madecassoside and asiaticoside from Centella asiatica. Department of Intellectual Property MoC ed. C07H 1/00 ed. Bangkok, Thailand: Chulalongkorn University; 2009
• 25 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
• 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
• 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
• 28 Chassaud LF, Fry BJ, Hawkins DR, Lewis JD, Sword IP, Taylor T, Hathway DE. The metabolism of asiatic acid, madecassic acid and asiaticoside in the rat. Arzneimittelforschung 1971; 21: 1379-1384