Pharmacokinetic Properties of Pure Xanthones in Comparison to a Mangosteen Fruit Extract in Rats

Abstract

The xanthones α-mangostin and γ-mangostin are the major bioactive compounds in Garcinia mangostana (mangosteen) fruit extracts. Previously, we reported the pharmacokinetic properties of α-mangostin in rats. The purpose of this follow-up study was to compare the pharmacokinetic characteristics of α-mangostin and γ-mangostin in rats if administered as either a pure compound or as a component of a mangosteen fruit extract. The absolute bioavailability of γ-mangostin when administered as a pure compound was determined by giving male Sprague Dawley rats 2 mg/kg γ-mangostin intravenously or 20 mg/kg orally. A 160 mg/kg aliquot of mangosteen fruit extract was administered, containing α- and γ-mangostin doses equal to 20 mg/kg and 4.5 mg/kg of each pure compound, respectively. Plasma samples were collected for both pharmacokinetic studies, and compound concentrations were measured by LC-MS/MS. The pharmacokinetic of γ-mangostin after intravenous administration followed a two-compartment body model. The half-life of the distribution phase was 2.40 min, and that of the elimination phase was 1.52 h. After oral administration, both α- and γ-mangostin underwent intensive first-pass metabolism, and both compounds were conjugated rapidly after oral administration. When given as an extract, the total absorption of α- and γ-mangostin was not increased, but the conjugation was slower, resulting in increased free (unconjugated) compound exposure when compared to pure compound administration. Since reported beneficial biological activities of mangosteen xanthones are based on the free, unconjugated compounds, food supplements containing mangosteen fruit extracts should be preferred over the administration of pure xanthones.

Key words

Garcinia mangostana - Clusiaceae - γ-mangostin - mangosteen extract - pharmacokinetics - conjugation

• References

• 1 Ji X, Avula B, Khan IA. Quantitative and qualitative determination of six xanthones in Garcinia mangostana L. by LC-PDA and LC-ESI-MS. J Pharm Biomed Anal 2007; 43: 1270-1276
• 2 Obolskiy D, Pischel I, Siriwatanametanon N, Heinrich M. Garcinia mangostana L.: A phytochemical and pharmacological review. Phytother Res 2009; 23: 1047-1065
• 3 Pedraza-Chaverri J, Cardenas-Rodriguez N, Orozco-Ibarra M, Perez-Rojas JM. Medicinal properties of mangosteen (Garcinia mangostana). Food Chem Toxicol 2008; 46: 3227-3239
• 4 Destandau E, Toribio A, Lafosse M, Pecher V, Lamy C, Andre P. Centrifugal partition chromatography directly interfaced with mass spectrometry for the fast screening and fractionation of major xanthones in Garcinia mangostana . J Chromatogr A 2009; 1216: 1390-1394
• 5 Fang L, Liu Y, Zhuang H, Liu W, Wang X, Huang L. Combined microwave-assisted extraction and high-speed counter-current chromatography for separation and purification of xanthones from Garcinia mangostana . J Chromatogr B Analyt Technol Biomed Life Sci 2011; 879: 3023-3027
• 6 Chin YW, Kinghorn AD. Structural characterization, biological effects, and synthetic studies on xanthones from mangosteen (Garcinia mangostana), a popular botanical dietary supplement. Mini Rev Org Chem 2008; 5: 355-364
• 7 Pothitirat W, Chomnawang MT, Supabphol R, Gritsanapan W. Free radical scavenging and anti-acne activities of mangosteen fruit rind extracts prepared by different extraction methods. Pharm Biol 2010; 48: 182-186
• 8 Jung HA, Su BN, Keller WJ, Mehta RG, Kinghorn AD. Antioxidant xanthones from the pericarp of Garcinia mangostana (mangosteen). J Agric Food Chem 2006; 54: 2077-2082
• 9 Chen LG, Yang LL, Wang CC. Anti-inflammatory activity of mangostins from Garcinia mangostana . Food Chem Toxicol 2008; 46: 688-693
• 10 Chomnawang MT, Surassmo S, Wongsariya K, Bunyapraphatsara N. Antibacterial activity of thai medicinal plants against methicillin-resistant Staphylococcus aureus . Fitoterapia 2009; 80: 102-104
• 11 Watanapokasin R, Jarinthanan F, Jerusalmi A, Suksamrarn S, Nakamura Y, Sukseree S, Uthaisang-Tanethpongtamb W, Ratananukul P, Sano T. Potential of xanthones from tropical fruit mangosteen as anti-cancer agents: Caspase-dependent apoptosis induction in vitro and in mice. Appl Biochem Biotechnol 2010; 162: 1080-1094
• 12 Moongkarndi P, Kosem N, Kaslungka S, Luanratana O, Pongpan N, Neungton N. Antiproliferation, antioxidation and induction of apoptosis by Garcinia mangostana (mangosteen) on SKBR3 human breast cancer cell line. J Ethnopharmacol 2004; 90: 161-166
• 13 Balunas MJ, Su B, Brueggemeier RW, Kinghorn AD. Xanthones from the botanical dietary supplement mangosteen (Garcinia mangostana) with aromatase inhibitory activity. J Nat Prod 2008; 71: 1161-1166
• 14 Chin YW, Jung HA, Chai H, Keller WJ, Kinghorn AD. Xanthones with quinone reductase-inducing activity from the fruits of Garcinia mangostana (mangosteen). Phytochemistry 2008; 69: 754-758
• 15 Nabandith V, Suzui M, Morioka T, Kaneshiro T, Kinjo T, Matsumoto K, Akao Y, Iinuma M, Yoshimi N. Inhibitory effects of crude alpha-mangostin, a xanthone derivative, on two different categories of colon preneoplastic lesions induced by 1,2-dimethylhydrazine in the rat. Asian Pac J Cancer Prev 2004; 5: 433-438
• 16 Udani JK, Singh BB, Barrett ML, Singh VJ. Evaluation of mangosteen juice blend on biomarkers of inflammation in obese subjects: A pilot, dose finding study. Nutr J 2009; 8: 48
• 17 Kondo M, Zhang L, Ji H, Kou Y, Ou B. Bioavailability and antioxidant effects of a xanthone-rich mangosteen (Garcinia mangostana) product in humans. J Agric Food Chem 2009; 57: 8788-8792
• 18 Li L, Brunner I, Han AR, Hamburger M, Kinghorn AD, Frye R, Butterweck V. Pharmacokinetics of alpha-mangostin in rats after intravenous and oral application. Mol Nutr Food Res 2011; 55 (Suppl. 01) S67-S74
• 19 Chitchumroonchokchai C, Riedl KM, Suksumrarn S, Clinton SK, Kinghorn AD, Failla ML. Xanthones in mangosteen juice are absorbed and partially conjugated by healthy adults. J Nutr 2012; 142: 675-680
• 20 FDA. Guidance for industry – bioanalytical method validation. Available at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070107.pdf Accessed March 4, 2013.
• 21 Manach C, Williamson G, Morand C, Scalbert A, Remesy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am J Clin Nutr 2005; 81: 230S-242S
• 22 Gibson G, Skett P. Introduction to drug metabolism. 3rd. edition. Cheltenham: Nelson Thornes; 2001: 64-71
• 23 Mulder GJ. Glucuronidation and its role in regulation of biological activity of drugs. Annu Rev Pharmacol Toxicol 1992; 32: 25-49
• 24 Mahabusarakam W, Kuaha K, Wilairat P, Taylor WC. Prenylated xanthones as potential antiplasmodial substances. Planta Med 2006; 72: 912-916
• 25 Ho CK, Huang YL, Chen CC. Garcinone e, a xanthone derivative, has potent cytotoxic effect against hepatocellular carcinoma cell lines. Planta Med 2002; 68: 975-979
• 26 Balunas MJ, Kinghorn AD. Natural compounds with aromatase inhibitory activity: An update. Planta Med 2010; 76: 1087-1093
• 27 Han AR, Kim JA, Lantvit DD, Kardono LB, Riswan S, Chai H, Carcache de Blanco EJ, Farnsworth NR, Swanson SM, Kinghorn AD. Cytotoxic xanthone constituents of the stem bark of Garcinia mangostana (mangosteen). J Nat Prod 2009; 72: 2028-2031
• 28 Sampath PD, Vijayaragavan K. Ameliorative prospective of alpha-mangostin, a xanthone derivative from Garcinia mangostana against beta-adrenergic cathecolamine-induced myocardial toxicity and anomalous cardiac TNF-alpha and COX-2 expressions in rats. Exp Toxicol Pathol 2008; 60: 357-364
• 29 Shibata MA, Iinuma M, Morimoto J, Kurose H, Akamatsu K, Okuno Y, Akao Y, Otsuki Y. Alpha-mangostin extracted from the pericarp of the mangosteen (Garcinia mangostana Linn) reduces tumor growth and lymph node metastasis in an immunocompetent xenograft model of metastatic mammary cancer carrying a p 53 mutation. BMC Med 2011; 9: 69
• 30 Doi H, Shibata MA, Shibata E, Morimoto J, Akao Y, Iinuma M, Tanigawa N, Otsuki Y. Panaxanthone isolated from pericarp of Garcinia mangostana suppresses tumor growth and metastasis of a mouse model of mammary cancer. Anticancer Res 2009; 29: 2485-2495
• 31 Kosem N, Ichikawa K, Utsumi H, Moongkarndi P. In vivo toxicity and antitumor activity of mangosteen extract. J Nat Med 2013; 67: 255-263
• 32 Chitchumroonchokchai C, Thomas-Ahner JM, Li J, Riedl KM, Nontakham J, Suksumrarn S, Clinton SK, Kinghorn AD, Failla ML. Anti-tumorigenicity of dietary alpha-mangostin in an HT-29 colon cell xenograft model and the tissue distribution of xanthones and their phase II metabolites. Mol Nutr Food Res 2013; 57: 203-211
• 33 Han S, Chin Y, Choi Y. Comparison of pharmacokinetic parameters of α-mangostin after administration of α-mangostin and mangosteen extract in mouse. Planta Med 2012; 78: PH27
• 34 Mohamed ME, Frye RF. Effects of herbal supplements on drug glucuronidation. Review of clinical, animal, and in vitro studies. Planta Med 2011; 77: 311-321