pubs.acs.org/JAFC Published on Web 11/16/2009 © 2009 American Chemical Society 546 J. Agric. Food Chem. 2010, 58, 546–551 DOI:10.1021/jf9026124 Lymphatic Absorption of Quercetin and Rutin in Rat and Their Pharmacokinetics in Systemic Plasma I-LIN CHEN, † YUNG-JEN TSAI, † CHIH-MIN HUANG, † AND TUNG-HU TSAI* ,†,§,# † Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei, Taiwan, § Graduate Institute of Acupuncture Science, China Medical University, Taichung, Taiwan, and # Department of Education and Research, Taipei City Hospital, Taipei, Taiwan Substances and macromolecules absorbed by the lymphatic system avoid hepatic first-pass effect and directly enter the blood circulation system. In this study, an anesthetized, mesenteric lymphatic/ duodenum-cannulated rat model was used to investigate the role of lymphatic absorption with intraduodenally administered drugs. Quercetin and rutin were administered, respectively, at dosages of 30 and 300 mg/kg intraduodenally. Lymph and plasma samples were collected every 30 min. These samples were prepared by protein precipitation and then analyzed by high-performance liquid chromatography with a photodiode array detector (HPLC-PDA) and verified by LC tandem mass spectrometry (LC-MS/MS). Quercetin was separated by a C18 reversed-phase column, and rutin was separated by a phenyl reverse-phase column. Pharmacokinetic parameters were calculated using the software WinNonlin Standard Edition Version. The maximum concentration (C max ) of quercetin recovered in lymph, 1.97 ( 0.96 μg/mL, was about 5-fold higher than that in plasma, 0.41 ( 0.08 μg/mL. The time to reach the highest concentration (T max ) of quercetin in lymph was 30 min longer than that in plasma. The maximun concentration (C max ) of rutin recovered in lymph, 0.86 ( 0.13 μg/mL, was slightly lower than that in plasma, 1.35 ( 0.37 μg/mL. The area under curve (AUC) of rutin recovered in lymph, 359 ( 41 min μg/mL, was about 2-fold higher than the AUC of rutin in plasma, 150 ( 22 min μg/mL. This phenomenon was due to the milder concentration decline of rutin in the lymphatic system. These results demonstrate the pharmacokinetic data of lymphatic and systemic absorption after intraduodenally administered quercetin and rutin. It is also the first report revealing the lymphatic absorption of rutin. Although both quercetin and rutin are absorbed and transported mainly via the blood circulation system, the AUC of these two drugs in lymph fluid appeared higher than their respective AUC in plasma. KEYWORDS: Herbal ingredient; intraduodenal administration; lymphatic absorption; pharmacokine- tics; quercetin; rutin INTRODUCTION The lymphatic system is part of the body’s fluid circulation system, composed of nodules and ducts that are recognized as lymph nodes and lymph ducts. Its functions include immune system regulation and maintenance, extracellular fluid absorp- tion and recirculation, specific cellular and macromolecular particle transportation, nutrient absorption from intestinal tracts, and so on ( 1 ). Of late, the subject of lymphatic absorption has gained more and more attention in the fields of pharmacology and nutrition ( 2 , 3 ). This is due to the role of the lymphatic system not only as a route of nutrient absorption and macroparticle uptake but also as a way for molecules to be absorbed into the body while avoiding the hepatic first-pass effect ( 4 ). Substances absorbed by lacteal ducts enter the mesenteric lymph duct and then pass into the cisterna chyli, where lymph fluid from the intestines and lower body merge together. From the cisterna chyli lymph fluid flows upward into the thoracic duct. Lymph will enter the blood circulation at the junction of the subclavian vein and the internal jugular vein ( 5 ). By following this route, drugs or other exogenous substances may enter whole-body blood circulation without hepatic fist-pass metabolism via lymphatic absorption. This is important for drugs and substances that are easily metabolized by hepatic enzymes. Research about lymphatic absorption has discovered that lipophilic, macromolecular substances are more likely to be transported via the lymphatic system ( 6 -9 ). As an example, halofantrine is the most well-known drug that is mainly trans- ported through the lymphatic system ( 10 ). This discovery pro- vided a new vision for researchers, showing that other than blood capillaries there is another pathway for absorbing drugs adminis- tered orally. Topics of pharmacokinetic study on lymphatic absorption of orally administered drugs are emerging as new fields of investigation, and gastrointestinal lymphatic absorption indeed may be an alternative for drug administration in the future. However, due to the complex nature of the lymphatic *Corresponding author [fax (886-2) 2822-5044; telephone (886-2) 2826-7115; e-mail thtsai@ym.edu.tw].