Serum Concentrations of Anthraquinones after Intake of Folium Sennae and Potential Modulation on P-glycoprotein

Abstract

Folium Sennae (leaves of Cassia angustifolia or senna) is a laxative and a component in diets for weight control. It contains a variety of anthranoids such as sennosides, aloe-emodin, and rhein. In order to measure the serum concentrations of senna anthranoids, Sprague-Dawley rats were orally administered with single dose and multiple doses of Folium Sennae. The concentrations of anthranoids in serum were determined by HPLC method before and after hydrolysis with sulfatase and β-glucuronidase. The results showed that in the serum, aloe-emodin glucuronides and rhein glucuronides were the major metabolites. Traces of rhein free form were present transiently during the early phase, whereas the free form of aloe-emodin was not detected. We also evaluated the modulation effect of Folium Sennae on P-glycoprotein by using the LS 180 cell model which showed that it significantly inhibited P-glycoprotein by 16–46 %. In conclusion, senna anthranoids were rapidly and extensively metabolized to rhein glucuronides and aloe-emodin glucuronides in rats. Folium Sennae ingestion inhibited the efflux function of P-glycoprotein in the intestine.

Key words

Cassia angustifolia - Fabaceae - aloe-emodin - rhein - glucuronides - P-glycoprotein

^* These authors contributed equally to the study.

• References

• 1 Silva CR, Monteiro MR, Rocha HM, Ribeiro AF, Caldeira-de-Araújo A, Leitão AC, Bezerra R, Padula M. Assessment of antimutagenic and genotoxic potential of senna (Cassia angustifolia Vahl.) aqueous extract using in vitro assays. Toxicol In Vitro 2008; 22: 212-218
• 2 Ulbricht C, Conquer J, Costa D, Hamilton W, Higdon ER, Isaac R, Rusie E, Rychlik I, Serrano JM, Tanguay-Colucci S, Theeman M, Varghese M. An evidence-based systematic review of senna (Cassia senna) by the Natural Standard Research Collaboration. J Diet Suppl 2011; 8: 189-238
• 3 Chan TYK. Potential risks associated with the use of herbal anti-obesity products. Drug Saf 2009; 32: 453-456
• 4 Demirezer LO, Karahan N, Ucakturk E, Kuruuzum-Uz A, Guvenalp Z, Kazaz C. HPLC fingerprinting of sennosides in laxative drugs with isolation of standard substances from some senna leaves. Rec Nat Prod 2011; 5: 261-270
• 5 Franz G. The senna drug and its chemistry. Pharmacology 1993; 47 (Suppl. 01) S2-S6
• 6 Hattori M, Namba T, Akao T, Kobashi K. Metabolism of sennosides by human intestinal bacteria. Pharmacology 1988; 36: 172-179
• 7 de Witte P, Lemli L. The metabolism of anthranoid laxatives. Hepatogastroenterology 1990; 37: 601-605
• 8 Dewitte P. Metabolism and pharmacokinetics of anthranoids. Pharmacology 1993; 47: 86-97
• 9 Werner C, Merz B. Assessment report on Cassia senna L. and Cassia angustifolia Vahl, folium. European Medicines Agency. Available at http://www.ema.europa.eu/ema/index Accessed April 27, 2007.
• 10 Laitinen L, Takala E, Vuorela H, Vuorela P, Kaukonen AM, Marvola M. Anthranoid laxatives influence the absorption of poorly permeable drugs in human intestinal cell culture model (Caco-2). Eur J Pharm Biopharm 2007; 66: 135-145
• 11 Giacomini KM, Huang SM. Transporters in drug development and clinical pharmacology. Clin Pharmacol Ther 2013; 94: 3-9
• 12 Goppel M, Franz G. Stability control of senna leaves and senna extracts. Planta Med 2004; 70: 432-436
• 13 Maryadele JO. The Merck Index. 13th edition. New Jersey: Merck Research Lab; 2001: 1516
• 14 Tukey RH, Strassburg CP. Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annu Rev Pharmacol Toxicol 2000; 40: 581-616
• 15 Shia CS, Juang SH, Tsai SY, Chang PH, Kuo SC, Hou YC, Chao PDL. Metabolism and pharmacokinetics of anthraquinones in Rheum palmatum in rats and ex vivo antioxidant activity. Planta Med 2009; 75: 1386-1392
• 16 Tsuji A. Transporter-mediated drug interactions. Drug Metab Pharmacokinet 2002; 17: 253-274
• 17 Valli G, Giardina EG. Benefits, adverse effects and drug interactions of herbal therapies with cardiovascular effects. J Am Coll Cardiol 2002; 39: 1083-1095
• 18 Wang MT, Li IH, Lee WJ, Huang TY, Leu HB, Chan AL. Exposure to sennoside-digoxin interaction and risk of digoxin toxicity: a population-based nested case-control study. Eur J Heart Fail 2011; 13: 1238-1243
• 19 Mosmann T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983; 65: 55-63
• 20 Yang SY, Tsai SY, Hou YC, Chao PDL. Inductive modulation on P-glycoprotein and cytochrome 3A by resveratrol, a constituent of grapes. Food Chem 2012; 133: 683-688