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Abstract: Ethnopharmacological relevance: Da-Huang-Fu-Zi-Tang (DHFZT) is a crucial TCM formula commonly used for the treatment of acute pancreatitis in Chinese clinical application. Our previous work found that DHFZT could act against pancreatic injury in rats with severe acute pancreatitis (SAP). The goal of this paper was to study the underlying correlations between the chemical spectra and the protective effect of DHFZT on pancreatic acinar cell to reveal the real bioactive compounds in DHFZT. Materials and methods: The fingerprint chromatograms of rat serum after oral administration of DHFZT were established by UHPLC-ESI-Q-TOF-MS technique. At the same time, the model of anti-acute pancreatitis on cells was established by adding 10?7 mol/L cerulein to AR42J cell line, and the protective effects of the serum on pancreatic acinar cell from injury was evaluated by detecting the efficacy of amylase. Then, the spectrum–effect relationships between UHPLC fingerprints and anti-acute pancreatitis activities were evaluated using canonical correlation analysis (CCA) statistical method. The chromatogram separation was performed on a C18 reversed phase UHPLC column (2.1mm×100mm, 3.5?m, Agilent), the column temperature was set at 35°C. The mobile phase consisted of 0.1% formic acid and acetonitrile with gradient elution. The serum samples were analyzed both in negative and positive ion mode. The mother and productive ions were scanned within the mass range of m/z 100–1200 and 50–1200, respectively. A thorough analysis of a great deal of information of the constituents in the rat serum was undertaken. The structure identification of the detected compounds was achieved by using high resolution MS values as well as the MS/MS fragments. Results: Eighteen peaks in rat serum after oral administration of DHFZT were detected within only 30min recorded chromatograms. The structure of the 18 compounds were then given out, of which 10 were the original form of compounds absorbed from DHFZT, 8 were the metabolites of the compounds existed in rat serum. According to the CCA results, talatisamine, rhein glucoside, rhein isomer methylation, hypaconine, hydroxyl-chrysophanol, emodin glucuronide conjugation, and chrysophanol glucuronide conjugation were finally found to be the main anti-acute pancreatitis components in DHFZT. Conclusions: The model presented in this paper successfully discovered the spectrum–effect relationships of DHFZT, which showed a representative way to discover the primary active ingredients from the complicated herbal drugs. [Copyright &y& Elsevier]

Ethnopharmacological relevance Pharmacokinetic studies on traditional Chinese medicine are useful to evaluate and predict the drug efficacy and safety. The renal impairment may affect drug clearance and other pharmacokinetic processes which can increase toxicity and drug to drug interactions or cause ineffective therapy. Pharmacokinetic studies in pathological status rats might be meaningful for revealing the action mechanism and improving clinical medication of the herb medicine. Materials and methods A highly sensitive and rapid ultra-performance liquid chromatography–mass spectrometry (UPLC–MS) method with multiple-reaction monitoring (MRM) mode was developed and validated for simultaneous quantitation of morroniside and loganin in normal and doxorubicin-induced chronic kidney disease (CKD) rat plasma after oral administration of Shanzhuyu (fruit of Cornus officinalis ) extract. Results Both calibration curves gave satisfactory linearity ( r >0.99) at linear range of 1.96–1962.5 ng mL −1 for morroniside, 1.53–1531.25 ng mL −1 for loganin. The precision and accuracy of the in vivo study were assessed by intra-day and inter-day assays. The percentages of relative standard deviation (RSD) were all within 9.58% and the accuracy (RE) was in the −6.02% to 8.11% range. The extraction recoveries of morroniside, loganin and internal standard (IS) were all >67.62% and the matrix effects ranged from 95.07% to 102.75%. Conclusions The pharmacokinetic behavior of morroniside and loganin in normal and CKD rat plasma was determined in this paper. The significant different pharmacokinetic parameters might partly result from the changes of P-glycoprotein and metabolic enzymes in the pathological state. The pharmacokinetic research in the pathological state might provide more useful information to guide the clinical usage of the herb medicine. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Jiao-Tai-Wan (JTW), an important herbal formula consists of Rhizoma coptidis and Cortex cinnamomi powder, is a famous prescription which has been used for centuries to treat insomnia in Traditional Chinese Medicine. The purpose of this study is to compare the pharmacokinetic properties of five protoberberine-type alkaloids (i.e. berberine, palmatine, coptisine, epiberberine and jatrorrhizine), the main bioactive constituents in JTW, between normal and insomnic rats. We also investigate the differences between single-dose and multiple-dose pharmacokinetics of five protoberberine-type alkaloids. Materials and methods: The insomnic rat models were induced by intraperitoneal injection of one-dose para-chlorophenylalanine acid (PCPA). Quantification of five protoberberine-type alkaloids in rat plasma was achieved by using a rapid LC–MS/MS method. Plasma samples were collected at different time points to construct pharmacokinetic profiles by plotting drug concentration versus time and estimate pharmacokinetic parameters. An unpaired Student׳s t test was used for comparisons with SPSS 17.0. Results: The five protoberberine-type alkaloids of single-dose normal groups had slow absorption and low bioavailability, as well as a delay of peak time. In the single-dose oral administration, the C max and T max of five ingredients in insomnic rats had significant differences compared with those of normal rats. In the multiple-dose oral administration, the pharmacokinetic parameters of five protoberberine-type alkaloids varied greatly in insomnic rats. In the normal rats, there were significant differences (P<0.05) in the principal pharmacokinetic parameters such as C max and T max between single-dose and multiple-dose oral administration. In the insomnic rats, the five ingredients of multiple-dose groups showed better absorption than the single-dose groups. Particularly, three peaks were observed in multiple-dose model group of plasma–concentration curves. Conclusions: The pharmacokinetic behavior of five protoberberine-type alkaloids was described in this paper. In both normal groups and model groups, the pharmacokinetic behavior of multiple-dose had significant differences comparing with the single-dose; either single-dose or multiple-dose, the pharmacokinetic behavior of insomnic rats had significant differences comparing the normal rats. Multiple dosing may improve the absorption of JTW in insomnic rats, which will increase the bioavailability and bring into active role in therapeutical effect. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: The dried fruit of Psoralea corylifolia L. has been used to prevent and treat vitiligo, osteoporosis, arthralgia and asthma in Traditional Chinese Medicine for some 1600 years. Psoralen (P), isopsoralen (IP), psoralenoside (PO) and isopsoralenoside (IPO) are the major coumarins and coumarin-related benzofuran glycosides in Psoraleae Fructus, which have been reported to show estrogen-like activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. The first aim of this study is to develop a rapid, sensitive and selective ultra performance liquid chromatography tandem mass spectrometry (UPLC–MS/MS) approach for simultaneous determination of PO, IPO, P and IP in rat plasma and samples collected from in vitro incubation experiments. The second aim is to investigate the pharmacokinetic properties of PO, IPO, P and IP after oral administration of Psoralea corylifolia extract (PCE) to rats. The third aim is to confirm the biotransformation of PO to P or IPO to IP under gastrointestinal conditions. Materials and methods: A UPLC–MS/MS method with a C18 column and a mobile phase of methanol-0.1% aqueous formic acid was validated according to the criteria in FDA guidelines about bioanalytical method, which was developed to investigate the pharmacokinetic behavior of PO, IPO, P and IP from PCE and the metabolic pathways of PO to P or IPO to IP. Results: The criteria for establishment of a new UPLC–MS/MS method including selectivity, linearity, accuracy, precision, extraction recovery, matrix effect and stability were validated. This method was successfully applied to the quantitative determination of PO, IPO, P and IP in biological samples collected from both in vitro incubations and in vivo rat experiments. After oral administration of PCE to rat, pharmacokinetic parameters of these four compounds indicated that in vivo biotransformation may occur between PO and P or IPO and IP. Purified benzofuran glycosides fraction (PBGF), containing only PO and IPO, was orally administered to rats to further confirm the biotransformation of PO to P or IPO to IP under gastrointestinal conditions. An in vitro incubation study elucidated that PO and IPO were metabolized to P and IP by intestinal microflora through de-glucosylation. Conclusions: This paper developed a rapid, sensitive and selective UPLC–MS/MS method for simultaneous determination of PO, IPO, P and IP from PCE in biological samples, and investigated on their comprehensive in vivo and in vitro pharmacokinetic studies. These obtained results showed that the metabolism by intestinal bacteria plays an important role in pharmacological effects of orally administered PCE. [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: Acanthopanax sessiliflorus (Rupr. et Maxim.) Seem. is a shrub mainly present in China, Japan and Korea, the root bark of which is considered as one of the sources of Wujiapi and widely used for its various pharmacological effects. Aim of the study: A selective and sensitive UPLC–MS/MS method was developed and validated for the determination and pharmacokinetic study of asarinin, sesamin, helioxanthin and savinin in rat plasma. Materials and methods: Sample preparation involved a liquid–liquid extraction of the analytes with methyl tert-butyl ether (MTBE). LC separation was achieved on a UPLC C18 column at 30°C with a mobile phase consisting of methanol–2mM ammonium acetate (68:32, v/v). The detection was accomplished by multiple-reaction monitoring (MRM) scanning with electrospray ionization (ESI) source operating in the positive ionization mode. The optimized mass transition ion-pairs (m/z) monitored for asarinin, sesamin, helioxanthin, savinin and IS were 372.2/233.0, 372.2/233.0, 349.1/319.0, 352.9/334.9 and 180.0/109.7, respectively. Results: The current LC–MS/MS assay was validated for linearity, intra-day and inter-day precisions, accuracy, extraction recovery and stability and was suitable for pharmacokinetic studies of the four lignans after oral administration of Acanthopanax sessiliflorus extract. The time to reach the maximum plasma concentration (T max) was 2.50±0.15h for asarinin, 1.94±0.28 for sesamin, 2.22±0.48h for helioxanthin and 2.83±0.29h for savinin. The elimination half-time (t 1/2) of asarinin, sesamin, helioxanthin and savinin was 6.08±1.10, 11.69±0.50, 7.16±0.52 and 6.26±0.57h, respectively. Conclusion: This paper described a simple, sensitive and validated UPLC–MS/MS method for simultaneous determination of four lignans in rat plasma after oral administration of Acanthopanax sessiliflorus extract, and investigated on their pharmacokinetic studies as well. [Copyright &y& Elsevier]