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Journal of Pharmaceutical and Biomedical Analysis 83 (2013) 108–121

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Journal of Pharmaceutical and Biomedical Analysis 83 (2013) 108–121 Journal of Pharmaceutical and Biomedical Analysis 83 (2013) 108–121 Contents lists available at SciVerse ScienceDirect Journal of Pharmaceutical and Biomedical Analysis jou rnal homepage: www.elsevier.com/locate/jpba The profiling and identification of the absorbed constituents and metabolites of Paeoniae Radix Rubra decoction in rat plasma and urine by the n HPLC–DAD–ESI-IT-TOF-MS technique: A novel strategy for the systematic screening and identification of absorbed constituents and metabolites from traditional Chinese medicines 1 1 Jing Liang , Feng Xu , Ya-Zhou Zhang, Shuai Huang, Xin-Yu Zang, Xin Zhao, Lei Zhang, ∗ Ming-Ying Shang, Dong-Hui Yang, Xuan Wang, Shao-Qing Cai State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, No. 38 Xueyuan Road, Beijing 100191, China a r t i c l e i n f o a b s t r a c t Article history: Paeoniae Radix Rubra (PRR, the dried roots of Paeonia lactiflora) is a commonly used traditional Chinese Received 23 January 2013 medicine (TCM). A clear understanding of the absorption and metabolism of TCMs is very important Received in revised form 13 April 2013 in their rational clinical use and pharmacological research. To find more of the absorbed constituents Accepted 16 April 2013 and metabolites of TCMs, a novel strategy was proposed. This strategy was characterized by the fol- Available online 9 May 2013 lowing: the establishment and utilization of the databases of parent compounds, known metabolites and characteristic neutral losses; the comparison of base peak chromatograms and ClogPs; and the use Keywords: n of the HPLC–DAD–ESI-IT-TOF-MS technique. This strategy was first applied to screen and identify the Paeonia lactiflora Paeoniflorin absorbed constituents and metabolites of PRR decoction and paeoniflorin in rats. In total, 13 new absorbed (Epi)catechin constituents and 90 new metabolites of PRR decoction were detected. Among these metabolites, the struc- Gallic acid tures of 70 metabolites were identified, and the conjugation types and structure skeletons of the other Effective forms 20 metabolites were preliminarily determined. Moreover, 35 new metabolites of some constituents of PRR, i.e., 22 new metabolites of paeoniflorin, 10 new metabolites of gallic acid-related compounds, 1 new metabolite of (epi)catechin-related compounds, and 2 new metabolites of other compounds, were reported for the first time. The results also indicated that (epi)catechin-related compounds, gallic acid- related compounds and paeoniflorin were the main precursors of these metabolites. Phase I reactions (dehydroxylation, decarboxylation, dehydrogenation) and phase II reactions (sulfation, glucuronidation and methylation) were observed as the main metabolic pathways of PRR. According to the literature, the 11 absorbed constituents and 11 metabolites have various bioactivities. This study is the first to explore the absorption and metabolism of PRR decoction, and the result also is a notable improvement in the dis- covery of paeoniflorin metabolites in vivo. These findings enhance our understanding of the metabolism and Effective forms (the truly active structures) of PRR decoction and paeoniflorin. © 2013 Elsevier B.V. All rights reserved. 1. Introduction Pall. or Paeonia veitchii Lynch. According to TCM theory, PRR can remove heat from blood, can eliminate blood stasis, and can relieve Paeoniae Radix Rubra (PRR), which is one of the commonly pain. Recent pharmacological studies indicate that PRR has various used traditional Chinese medicines (TCMs) and is called Chishao bioactivities, such as anti-platelet agglutination, anti-thrombus, in Chinese, is derived from the dried roots of Paeonia lactiflora anticoagulation, anti-atherosclerosis, heart and liver protection, and anti-tumor properties [1]. With respect to the chemical con- stituents of PRR, more than 150 compounds have been isolated and identified to date, among which monoterpene glycosides and ∗ Corresponding author at: Department of Natural Medicines, School of Pharma- phenolic compounds are considered to be the major constituents ceutical Sciences, Peking University Health Science Center, No. 38 Xueyuan Road, [2,3]. Haidian District, Beijing 100191, China. Tel.: +86 10 82801693; Many investigations on PRR have been conducted in the fields of fax: +86 10 82801693. phytochemistry, pharmacology and clinical application. However, E-mail address: [email protected] (S.-Q. Cai). 1 until now, little has been known about either how many and which These authors contributed equally to this work. 0731-7085/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jpba.2013.04.029 J. Liang et al. / Journal of Pharmaceutical and Biomedical Analysis 83 (2013) 108–121 109 constituents are absorbed into the blood after the administration of (Shanghai, China). The purities of all standards were above 98% PRR decoction or what the final fate of the decoction is in vivo. This based on HPLC analysis (area normalization method). Acetonitrile presents a significant obstacle for deeper pharmacological mech- (Merck KGaA, Darmstadt, Germany) and formic acid (Mreda anism studies and increasing the clinical applications of PRR. As Technology, Beijing, China) were of HPLC-grade. De-ionized water a result, it is extremely urgent to thoroughly profile the absorbed was prepared using a Milli-Q water purification system (Millipore, constituents and metabolites of PRR. Billerica, MA, USA). Analytical grade sodium carboxymethyl cel- Paeoniflorin is one of the main active constituents in PRR lulose (CMC-Na) was purchased from Kermel Chemical Reagents decoction and has been used as a phytochemical marker for the Development Centre (Kermel, Tianjin, China). Paeoniae Radix quality control of PRR in Chinese Pharmacopoeia. Previous stud- Rubra (Sample No. 6902) was purchased from Baohua Chinese ies also showed that paeoniflorin exhibits diverse pharmacological Herbal Medicine Procurement Department (Heihe City, Hei- effects, such as anti-inflammatory, neuromuscular blocking, neuro- longjiang Province, China) in October 2011, and was authenticated protective, antihyperglycemic and cognition-enhancing effects [4]. as the roots of P. lactiflora Pall. by Prof. Shao-Qing Cai (School of However, studies have shown that paeoniflorin has a poor absorp- Pharmaceutical Sciences, Peking University). A voucher sample tion rate and very low bioavailability (3–4%) when administrated (No. 6902) was deposited in the Herbarium of Pharmacognosy, orally [5]. Previously, only 5 metabolites (7R-paeonimetabolin I, School of Pharmaceutical Sciences, Peking University. 7S-paeonimetabolin I, 7R-paeonimetabolin II, 7S-paeonimetabolin II and paeoniflorgenin) of paeoniflorin had been found, and all of 2.2. Preparation of the PRR decoction and paeoniflorin solution these metabolites were formed by intestinal bacteria [6–8]. To gain a more comprehensive understanding of the metabolism of PRR and Two hundred grams of PRR was cut into small pieces (approxi- the Effective forms (truly active structures) of paeoniflorin, further mately 0.5 cm length) and immersed in 2000 mL de-ionized water research on the metabolism of paeoniflorin was deemed necessary. for 0.5 h, then heated to boiling and maintained for 0.5 h. The aque- Profiling the absorbed constituents and metabolites of a TCM is ous extract was filtered, and the residue was decocted twice with difficult, because (1) endogenous metabolites and proteins often 1600 mL and 1200 mL de-ionized water under the same conditions. interfere. Additionally, the concentrations of the absorbed con- The filtered supernatants were combined and evaporated to 300 mL stituents and metabolites are quite low, increasing the complexity and then were freeze-dried, yielding 70 g dried powder by a SIM of their determination in biological samples; (2) their structures FD8-10B freezer dryer (SIM International Group Co. Ltd., Newark, are highly diverse, and many are unknown metabolites, whose DE, USA) for animal studies. The dried powder was characterized by n structural information has not been previously reported; hence, the LCMS technique, and the major constituents were identified unequivocally identifying their structures is a significantly chal- by comparison with reference substances or by the interpretation n lenging endeavor [9]. Therefore, a powerful and full-scale strategy of the LCMS data. The corresponding base peak chromatogram is essential; such a strategy must be applicable for the systematic is shown in Supplementary data – Fig. A1. Paeoniflorin powder screening and identification of the absorbed constituents and the was suspended in 0.5% CMC-Na solution and ultrasonic vibrated metabolites of TCMs. for 30 min (TP-150 ultrasonic cleaner, Tianpong Electricity New The primary aim of studies on the absorption and metabolism of Technology Co., Beijing, China) before administration. TCMs is to understand better their pharmacological mechanism and clinical application. Absorbed constituents and circulating metabo- 2.3. Animals and drug administration lites ultimately reach biological targets, so they should be the main actors in explanations of the health effects of TCMs. Additionally, Eighteen male Sprague-Dawley rats (weighing in the range from the circulating metabolites are likely to possess different biologi- 250 to 300 g) were obtained from the Experimental Animal Cen- cal properties in comparison to those of their original compounds. ter of Peking University Health Science Center (Beijing, China). Therefore, it is necessary
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