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Ethnopharmacological Relevance: The traditional Chinese herbal remedy Atractylodes macrocephala Koidz is renowned for its purported gastrointestinal regulatory properties and immune-enhancing capabilities. Atractylenolide III (ATL III), a prominent bioactive compound in Atractylodes macrocephala Koidz, has demonstrated significant pharmacological activities. However, its impact on neuroinflammation, oxidative stress, and therapeutic potential concerning Alzheimer's disease (AD) remain inadequately investigated., Aim of the Study: This study aims to assess the plasma pharmacokinetics of ATL III in Sprague-Dawley (SD) rats and elucidate its neuropharmacological effects on AD via the PI3K/AKT/GSK3β pathway. Through this research, we endeavor to furnish experimental substantiation for the advancement of novel therapeutics centered on ATL III., Materials and Methods: The pharmacokinetic profile of ATL III in SD rat plasma was analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). AD models were induced in SD rats through bilateral intracerebroventricular (ICV) administration of streptozotocin (STZ). ATL III was administered at doses of 0.6 mg/kg, 1.2 mg/kg, and 2.4 mg/kg, while donepezil (1 mg/kg) served as control. Cognitive function assessments were conducted employing behavioral tests including the Morris Water Maze and Novel Object Recognition. Neuronal pathology and histological changes were evaluated through Nissl staining and Hematoxylin-Eosin (HE) staining, respectively. Oxidative stress levels were determined by quantifying malondialdehyde (MDA) content and total superoxide dismutase (T-SOD) activity. Molecular docking analysis was employed to explore the direct binding between ATL III and its relevant targets, followed by validation using Western blot (WB) experiments to assess the expression of p-Tau, PI3K, AKT, GSK3β, and their phosphorylated forms., Results: Within the concentration range of 5-500 ng/mL, ATL III demonstrated exceptional linearity (R 2  = 0.9991), with a quantification limit of 5 ng/mL. In male SD rats, ATL III exhibited a T max of 45 min, a t1/2 of 172.1 min, a C max of 1211 ng/L, and an AUC (0-t) of 156031 ng/L*min. Treatment with ATL III significantly attenuated Tau hyperphosphorylation in intracerebroventricular-streptozotocin (ICV-STZ) rats. Furthermore, ATL III administration mitigated neuroinflammation and oxidative stress, as evidenced by reduced Nissl body loss, alleviated histological alterations, decreased MDA content, and enhanced T-SOD activity. Molecular docking analyses revealed strong binding affinity between ATL III and the target genes PI3K, AKT, and GSK3β. Experimental validation corroborated that ATL III stimulated the phosphorylation of PI3K and AKT while reducing the phosphorylation of GSK3β., Conclusions: Our results indicate that ATL III can mitigate Tau protein phosphorylation through modulation of the PI3K/AKT/GSK3β pathway. This attenuation consequently ameliorates neuroinflammation and oxidative stress, leading to enhanced learning and memory abilities in ICV-STZ rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Arnicolide D, a potent sesquiterpene lactone from Centipeda minima, has emerged as a promising anticancer candidate, demonstrating significant efficacy in inhibiting cancer cell proliferation, inducing apoptosis, and suppressing metastasis across various cancer models. This comprehensive study delves into the molecular underpinnings of Arnicolide D's anticancer actions, emphasizing its impact on key signaling pathways such as PI3K/AKT/mTOR and STAT3, and its role in modulating cell cycle and survival mechanisms. Quantitative data from preclinical studies reveal Arnicolide D's dose-dependent cytotoxicity against cancer cell lines, including nasopharyngeal carcinoma, triple-negative breast cancer, and human colon carcinoma, showcasing its broad-spectrum anticancer potential. Given its multifaceted mechanisms and preclinical efficacy, Arnicolide D warrants further investigation in clinical settings to validate its therapeutic utility against cancer. The evidence presented underscores the need for rigorous pharmacokinetic and toxicological studies to establish safe dosing parameters for future clinical trials., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell-mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non-ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I-mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient-derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.

Background: Anisatin is a neurotoxic sesquiterpene dilactone wildly found in plants of the family Illiciaceae . Due to morphological similarities among Illiciaceae fruits, fatal poisonings are frequent., Objective: This study is aimed at developing a rapid, simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method to determine anisatin's bioavailability in mouse blood and the method's application to pharmacokinetics., Methods: Blood samples were preprocessed by protein precipitation using acetonitrile. Salicin (internal standard, IS) and anisatin were gradient-eluted by a mobile phase of methanol and water (0.1% formic acid) in a UPLC BEH C18 column. This step involved using an electrospray ionization source of anisatin at a mass-to-charge ratio (m/z) of 327.1 → 127.0 and IS at m/z 285.1 → 122.9 in the negative ion mode with multiple reaction monitoring., Results: The calibration curve ranged from 1 to 2000 ng/ml ( r > 0.995), with the method's accuracy ranging from 86.3% to 106.9%. Intraday and interday precision were lower than 14%, and the matrix effect was between 93.9% and 103.3%. The recovery rate was higher than 67.2%., Conclusions: The developed UPLC-MS/MS method was successfully used for a pharmacokinetic study of oral (1 mg/kg) and intravenous (0.5 mg/kg) administration of anisatin to mice-the absolute bioavailability of anisatin in the mouse blood was 22.6%., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Xi Bao et al.)

Free and glycosylated sesquiterpene lactones (SLs), which are abundant in leafy vegetables including Brussels/witloof chicory, possess health-promoting effects in vivo. However, the pharmacokinetics of dietary source of SLs remain largely unknown. In this open-label and single-dose trial, sixteen healthy volunteers consumed 150 g of Brussels/witloof chicory juice containing 48.77 μmol SLs in 5 min. Blood, urine, and fecal samples were collected before and after chicory consumption in 24 h. No SLs were detected in the serum, urine, and fecal samples before chicory consumption in all of the participants. Chicory consumption increased lactucin, 11β,13-dihydrolactucin, and their glucuronide/sulfate conjugates, rather than lactucopicrin and 11β,13-dihydrolactucopicrin, as well as glycosylated SLs in biological samples. The peak concentration of total SLs in serum reached 284.46 nmol/L at 1 h, while, in urine, this peak was 220.3 nmol between 2 and 6 h. The recovery of total SLs in blood, urine, and feces was 7.03%, 1.13%, and 43.76% of the ingested dose, respectively. Human fecal suspensions with intestinal microbiota degraded glycosylated SLs in chicory, and converted lactucopicrin and 11β,13-dihydrolactucopicrin to lactucin and 11β,13-dihydrolactucin, respectively. Collectively, Brussels/witloof chicory SLs are poorly bioavailable and they undergo partial gut microbial and phase II metabolism in humans.

Scope: Gut microbiota converts dietary phytochemicals into metabolites and modulates their health effects. The microbial metabolism of dietary terpenoids, as the sesquiterpene lactones of leafy vegetables, is unknown., Methods and Results: In vitro fermentation of lactucopicrin, lactucin, and romaine lettuce with gut microbiota from independent donors, show their extensive metabolism through untargeted metabolomics of the fecal incubations. Dehydroxylations and double bond hydrogenations are the main catabolic reactions. Isomers of dihydrolactucopicrin, tetrahydrolactucopicrin, and deoxylactucin, are observed after lactucopicrin metabolism. Tetrahydrolactucin and hexahydrolactucin are also found after lactucin metabolism. Lettuce fermentation shows similar metabolic conversions. Phase II conjugates of most of these metabolites are detected in the urine of healthy volunteers after escarole salad intake. Glucuronides, and sulfates, of dihydrolactucopicrin, tetrahydrolactucopicrin, dihydrolactucin, and deoxylactucin, are detected in the urine although with large inter-subject variability., Conclusion: This is the first report on the gut microbiota metabolism of sesquiterpene lactones in humans, and one of the first reports to describe that dietary terpenoids of widely consumed leafy vegetables are extensively catabolized by human gut microbiota. A large inter-subject variation in the metabolism of sesquiterpene lactones also reflects differences in gut microbiota composition. It suggests that inter-individual differences in their health effects should be expected., (© 2020 Wiley-VCH GmbH.)

Atractylodis rhizoma is a frequently-used traditional Chinese medicine in clinical practice, which have the effect of eliminating dampness and tonifying spleen. And after being processed with wheat bran, the dryness of A. rhizoma is reduced, and the function of tonifying spleen is enhanced. Atractylenolides are the major bioactive components of A. rhizoma, including atractylenolide I (AI), atractylenolide Ⅱ (AⅡ) and atractylenolide Ⅲ (AⅢ). The present study aimed to develope a new UPLC-MS/MS method for simultaneous quantification of three atractylenolides in rat urine, and applied to the excretory kinetics in Sprague-Dawley rats after oral administration of crude and processed A. rhizoma extracts. Analytes and internal standard were detected without interference in the multiple reaction monitoring (MRM) mode with positive electrospray ionization. The excretory kinetics parameters were calculated by a urine drug analysis model of drug and statistics (DAS) 3.2.8 software. The t1/2 and Ke of three atractylenolides had no significant difference between crude and processed A. rhizoma, but the recovery accumulative excretion of them in processed A. rhizoma were apparently higher than the crude ones (p<0.05, p<0.01). The results showed that only a small amount of atractylenolides excreted in urine and processing A. rhizoma with wheat bran by stir frying could promote the urinary excretion of them.

Background: Isoalantolactone and alantolactone are the main sesquiterpene lactones in Radix Inulae (dried root of Inula helenium L. or I. racemosa Hook. F.), which is a frequently utilized herbal medicine. They also occur in several plants and have various pharmacologic effects. However, they have been found to have poor oral bioavailability in rats., Objectives: To understand the intestinal absorptive characteristics of isoalantolactone and alantolactone as well specific influx and efflux transporters in their absorption., Methods: Bidirectional permeabilities of isoalantolactone and alantolactone were investigated across Caco-2 cell monolayers. Transport assays were performed using different concentrations of two lactones and specific inhibitors of ATP-binding cassette transporters and influx transporters., Results: The absorption permeability of isoalantolactone and alantolactone was high at the tested concentrations (5, 20 and 80 μmol/l), and the major permeation mechanism of both lactones was found to be passive diffusion with active efflux mediated by multidrug resistance-associated proteins (MRPs) and breast cancer resistance protein (BCRP)., Conclusion: Our results demonstrated that the absorption permeability of isoalantolactone and alantolactone was good in the Caco-2 cell model. The isoalantolactone and alantolactone absorption elucidated in this study provides useful information for further pharmacokinetics studies. Since low intestinal absorption can now be ruled out as a cause, further studies are needed to explain the low oral bioavailability of the two sesquiterpene lactones.

Atractylodes macrocephala Koidz (AMK) is a traditional Chinese medicine widely used in the treatment of various diseases, especially spleen deficiency. As the principle active constituents of AMK, however, the metabolites of Atractylenolide-III (A-lactone-III) have not been identified in rats yet. In this study, a three-step high throughput method based on UHPLC-Q-TOF-MS-MS was developed to profile and characterize the metabolites of A-lactone-III in rat feces, urine and plasma. The initial step was a full-scan that utilized a multiple mass defect filter (MMDF) combined with dynamic background subtraction (DBS). PeakView®1.2 and Metabolitepilot™1.5 software was then used to obtain data and seek possible metabolites. Finally, MS-MS spectra of the parent drug and possible metabolites were compared by the fragment ion peaks and retention times, which enabled metabolites to be identified. As a result, 53 metabolites were characterized in rats in vivo. The metabolic pathways of A-lactone-III were identified as including methylation, oxidation, hydroxylation, dihydroxylation, hydrogenation, glycosylation, sulfonation, and glucuronide, cysteine and N-acetylcysteine conjugation.

Atractylodis Rhizoma is the dried rhizome of Atractylodes lancea (Thunb.) DC. or Atractylodes chinensis (DC.) Koidz and is often processed by stir-frying with wheat bran to reduce its dryness and increase its spleen tonifying activity. However, the mechanism by which the processing has this effect remains unknown. To explain the mechanism based on the pharmacokinetics of the active compounds, a rapid, sensitive ultra-performance liquid chromatography-tandem mass spectrometry method was developed to analyze atractylenolides I, II, and III, and atractyloside A simultaneously in rat plasma after oral administration of raw and processed Atractylodis Rhizoma. Acetaminophen was used as the internal standard and the plasma samples were pretreated with methanol. Positive ionization mode coupled with multiple reaction monitoring mode was used to analyze the four compounds. The method validation revealed that all the calibration curves displayed good linear regression over the concentration ranges of 3.2⁻350, 4⁻500, 4⁻500, and 3.44⁻430 ng/mL for atractylenolides I, II, and III, and atractyloside A, respectively. The relative standard deviations of the intra- and inter-day precisions of the four compounds were less than 6% with accuracies (relative error) below 2.38%, and the extraction recoveries were more than 71.90 ± 4.97%. The main pharmacokinetic parameters of the four compounds were estimated with Drug and Statistics 3.0 and the integral pharmacokinetics were determined based on an area under the curve weighting method. The results showed that the integral maximum plasma concentration and area under the curve increased after oral administration of processed Atractylodis Rhizoma.

Costunolide and dehydrocostuslactone are the main active ingredients of Radix Aucklandiae (RA). An accurate and sensitive LC-MS/MS method was established to simultaneously determine contents of costunolide and dehydrocostuslactone in plasma. There were significant differences in pharmacokinetic parameters (AUC 0-t , C max,1 , C max,2 , T max,1 , Vd, and CL) of costunolide and dehydrocostuslactone between RA group and costunolide group or dehydrocostuslactone group. The relative bioavailability of costunolide or dehydrocostuslactone of RA extract was improved. As compared to normal group, the T max,2 values of dehydrocostuslactone of RA in gastric ulcer group were prolonged, while the C max,1 , C max,2 , and AUC 0-t values decreased.

Background: The SH-group at Cys-34 of human serum albumin (HSA) is a unique and accessible functional group that can be exploited for efficient linkage of a maleimide containing cytotoxic drug derivative to albumin. The specific maleimide chemistry used for production of the maleimide-linked albumin drug (MAD) is critical, however, to minimize the plasma concentration of "free" cytotoxic drug spontaneously released from albumin carrier thus decreasing dose-limiting host toxicity while enhancing the plasma half-life from minutes to days (ie, pharmacokinetic effect) and tissue concentration of the MAD in the extracellular cellular fluid at sites of cancer (ie, EPR effect)., Methods: To accomplish this goal, a chemical synthesis was developed using 2-fluoro-5-maleimidobenzoic acid to stably link the potent cytotoxic chemically modified analogue of the naturally occurring sesquiterpene γ-lactone, thapsigargin, 8-O-(12-aminododecanoyl)-8-O-debutanoyl thapsigargin (12ADT), to Cys-34 of albumin to produce 12ADT-MAD., Results: Using FITC-labeling, LC/MS analysis, and in vitro growth and clonogenic survival assays on a series of 6 human prostate cancer lines (LNCaP, LAPC-4, VCap, CWR22R v 1, PC3, and Du145), we documented that 12ADT-MAD is endocytosed by prostate cancer cells where it is degraded into its amino acids liberating cysteinyl-maleimide-12ADT which is both chemically stable at the acidic pH of 5.5 present in the endosome while retaining its high killing ability (IC 50 50 nM) via SERCA inhibition., Conclusions: Based upon these positive in vitro validation results, the in vivo efficacy versus host toxicity of this 12-ADT-MAD approach is presently being evaluated against a series of patient derived androgen responsive and castration resistant human xenografts in immune-deficient mice., (© 2018 Wiley Periodicals, Inc.)

In this study, an artichoke stem powder (ASP) was used at three concentrations (3%, 6% and 9%) in the formulation of new breads. The bioaccessibility of polyphenols and cynaropicrin from the ASP-enriched breads was evaluated in vitro by using a digestion model combined to high resolution mass spectrometry analysis. The overall total antioxidant capacity of the bioaccessible and unsolubilized fractions obtained during the intestinal steps and the potential ability to modulate α-glucosidase activity were tested. Data showed that 82% of totally bioaccessible polyphenols and 74% of cynaropicrin were released during the duodenal digestion whereas 88% of caffeic acid was released in the colon step. The antioxidant capacity and the α-glucosidase inhibitory activity of the duodenal extract correlated with the amount of ASP in the bread. Data demonstrated that ASP might be a valuable functional ingredient to create a reducing environment in the intestine and to partially modulate glucose metabolism., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

1,6-O,O-Diacetylbritannilactone is a natural sesquiterpene lactone isolated from Inula britannica that has displayed cytotoxic effects against several human cancer cell lines. In this study, a selective and sensitive liquid chromatography-tandem mass spectrometry (LC-MS-MS) method was developed for determination of 1,6-O,O-diacetylbritannilactone in rat plasma. Chromatographic separation was achieved on an Agilent C18 column (4.6 mm × 75 mm, 3.5 μm) with methanol and water (80:20, v/v) as the mobile phase. An ESI source was applied and operated in positive ion mode; selected-reaction monitoring was used for quantification using target fragment ions m/z 373.2→312.9 for 1,6-O,O-diacetylbritannilactone and m/z 331.2→144.1 for the IS. Calibration plots were linear in the range of 1.5-1350 ng/mL for 1,6-O,O-diacetylbritannilactone in rat plasma. Intra- and inter-day precisions were <8.5%, and the accuracy ranged from -2.7 to 12.8%. The LC-MS-MS method was successfully applied in a pharmacokinetic study of 1,6-O,O-diacetylbritannilactone in rats.

Alantolactone (AL) and isoalantolactone (IAL), two major active sesquiterpene lactones isolated from Radix Inulae extract, have a wide range of pharmacological activities. The predominant metabolic pathway of AL and IAL observed was glutathione (GSH) conjugation in vitro, which could occur in the absence of metabolic enzymes. Non-enzymatic conjugation with cysteine (Cys) couldalso be observed. Four metabolites (AL-GSH, AL-Cys, IAL-GSH, IAL-Cys) were subsequently isolated and confirmed by nuclear magnetic resonance (NMR). The results indicated that the thiol of GSH or Cys can be reacted with the exomethylene carbon atoms of α, β-unsaturated carbonyl of AL and IAL. After intravenous administration in rats, AL and IAL were extensively metabolized, and the exposure, as measured by area under the concentration-time curve (AUC), for AL-GSH, AL-Cys, IAL-GSH, and IAL-Cys was approximately 1.54-, 0.96-, 1.50-, and 0.91-fold that of the parent drug, respectively. The AUC ratio of metabolites to parent compounds of oral administration was 3.66-, 9.19-, 12.97-, and 9.92-fold that of the parent drug for the above metabolites, respectively. The bioavailability of AL-total (AL, AL-GSH, AL-Cys) and IAL-total (IAL, IAL-GSH, IAL-Cys) was, respectively, 8.39% and 13.07%, which was 3.62- and 6.95- fold that of AL (2.32%) and IAL (1.88%), respectively. The oral exposure will be underestimated if the parent drugs are tested alone. These findings provide useful information for preclinical safety evaluation, and for predicting AL and IAL metabolism in humans., (Copyright © 2017. Published by Elsevier B.V.)

Lychnopholide, a lipophilic sesquiterpene lactone, is efficacious in mice at the acute and chronic phases of Chagas disease. Conventional poly-ε-caprolactone (PCL) and long-circulating poly(D,L-lactide)-block-polyethylene glycol (PLA-PEG) nanocapsules containing lychnopholide were developed and characterized. Lychnopholide presented high association efficiency (>90%) with the nanocapsules. A new, fast and simple HPLC-UV-based bioanalytical method was developed, validated in mouse plasma and applied to lychnopholide quantification in in vitro release kinetics and pharmacokinetics. The nanocapsules had mean hydrodynamic diameters in the range of 100-250 nm, negative zeta potentials (-30 mV to -57 mV), with good physical stability under storage. Atomic force microscopy morphological analysis revealed spherical monodispersed particles and the absence of lychnopholide crystallization or aggregation. Association of lychnopholide to PLA-PEG nanocapsules resulted in a 16-fold increase in body exposure, a 26-fold increase in plasma half-life and a dramatic reduction of the lychnopholide plasma clearance (17-fold) in comparison with free lychnopholide. The improved pharmacokinetic profile of lychnopholide in long-circulating nanocapsules is in agreement with the previously reported improved efficacy observed in Trypanosoma cruzi-infected mice. The present lychnopholide intravenous dosage form showed great potential for further pre-clinical and clinical studies in Chagas disease and cancer therapies.

Lychnopholide is a sesquiterpene lactone usually obtained from Lychnophora and Eremanthus species and has pharmacological activities that include anti-inflammatory and anti-tumor. Lychnopholide isolated from Eremanthus matogrossenssis was analyzed in this study. The aims of this study were to develop and validate an analytical methodology by LC-MS/MS and to quantify lychnopholide in rat plasma. Chromatographic separation was achieved on a C18 column using isocratic elution with the mobile phase consisting of methanol and water (containing 0.1% formic acid) at a flow rate of 0.4 mL/min. The detection was performed in multiple-reaction monitoring mode using electrospray ionization in positive mode. The method validation was performed in accordance with regulatory guidelines and the results met the acceptance criteria. The linear range of detection was 10-200 ng/mL (r > 0.9961). The intra- and inter-day assay variability were <6.2 and <11.7%, respectively. The extraction recovery was approximately 63% using liquid-liquid extraction with chloroform. Lychnopholide was detected in plasma up to 60 min after intravenous administration in rats. This rapid and sensitive method for the analysis of the sesquiterpene lactone lychnopholide in rat plasma can be applied to pharmacokinetic studies of this compound. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

The pharmacokinetic properties of a new molecular entity are important aspects in evaluating the viability of the compound as a pharmacological agent. The sesquiterpene lactone lychnopholide exhibits important biological activities. The objective of this study was to characterize the pharmacokinetics of lychnopholide after intravenous administration of 1.65 mg/kg (n = 5) and oral administration of 3.3 mg/kg (n = 3) lychnopholide in rats (0.2 ± 0.02 kg in weight) through nonlinear mixed effects modeling and non-compartmental pharmacokinetic analysis. A highly sensitive analytical method was used to quantify the plasma lychnopholide concentrations in rats. Plasma protein binding of this compound was over 99 % as determined by a filtration method. A two-compartment body model plus three transit compartments to characterize the absorption process best described the disposition of lychnopholide after both routes of administration. The oral bioavailability was approximately 68 %. The clearance was 0.131 l/min and intercompartmental clearance was 0.171 l/min; steady-state volume of distribution was 4.83 l. The mean transit time for the absorption process was 9.15 minutes. No flip-flop phenomenon was observed after oral administration. The pharmacokinetic properties are favorable for further development of lychnopholide as a potential oral pharmacological agent., (Georg Thieme Verlag KG Stuttgart · New York.)

A simple and rapid ultra high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous determination of Atractylenolide I, II and III in rat plasma. Plasma samples were processed by liquid-liquid extraction with ethyl acetate, using schisandrin as internal standard (IS). Chromatographic separation was accomplished on a Thermo Hypersil GOLD C18 column (2.1mm×50mm, 1.9μm) with mobile phase consisting of acetonitrile and 0.1% formic acid-water (50:50, v/v). The detection was carried out by ESI-MS (positive ionization mode) and low-energy collision dissociation tandem mass spectrometric analyses using the multiple-reaction monitoring (MRM) scan mode. The quantification was performed using the transitions of the protonated molecule→product ion at m/z 231.0→185.1 for Atractylenolide I, at m/z 233.1→187.1 for Atractylenolide II and at m/z 249.1→231.1 for Atractylenolide III, respectively. Method validation revealed excellent linearity over investigated range together with satisfactory intra- and inter-day precision, accuracy, matrix effects and extraction recoveries. This method was successfully applied to the comparative pharmacokinetic study of Atractylenolide I, II and III in rat plasma after intragastric administration of Baizhufuling extract and Atractylodis extract., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Radix Inulae is endemic to China and has been used in traditional medicine to treat upper body pain, emesis and diarrhoea, and to eliminate parasites. Here, an UPLC-MS/MS method was developed and applied to study the pharmacokinetics, distribution and excretion of isoalantolactone and alantolactone, which are two main active sesquiterpene lactones in Radix Inulae, in Sprague-Dawley rats following oral administration of total Radix Inulae extract. Isoalantolactone, alantolactone and osthole (internal standard) were prepared using acetonitrile precipitation, and the separation of isoalantolactone and alantolactone was achieved by isocratic elution using water (containing 0.1% formic acid) and acetonitrile as the mobile phase using a ZORBAX Eclipse Plus C18 column. The total run time was 6.4 min. The present study showed poor absorption of isoalantolactone and alantolactone in vivo. The apparent Cmax, Tmax, T1/2 and total exposure (AUC0-12h) in rat plasma were 37.8 ng/mL, 120 min, 351.7 min and 6112.3 ng-min/mL for isoalantolactone and 25.9 ng/mL, 90 min, 321.0 min and 4918.9 ng-min/mL for alantolactone, respectively. It was shown that the highest concentration was achieved in the small intestine and feces clearance was shown to be the dominant elimination pathway of the lactones.

A HPLC-MS/MS multiple-reaction monitoring (MRM) quantitative analysis was made to establish a determination method for drug concentrations of costunolide (Co) and dehydrocostuslactone (De) in blood samples in the positive ion mode, with diazepam as the internal standard substance, in order to study the pharmacokinetic process of sesquiterpene lactones costunolide and dehydrocostuslactone after the oral administration of Weichang'an pills, and provide an theoretical basis for further studies on the substance basis for the anti-diarrhea effect of Weichang'an pills. In the blood samples, Co and De showed a good linearity within concentration ranges 0.700 0-769.7, 2.510-956.0 μg x L(-1), respectively. The results of precision, stability and recovery experiences proved the stability and reliability of the plasma concentration determination method. After the oral administration, the concentrations of Co and De in plasma increased with the increase in dose, with T(max) between 10.65-12.98 h, indicating a long time to reach peak plasma concentrations; C(max) of costunolide and dehydrocostuslactone ranged between 3.750-5.450,15.34-44.52 μg x L(-1), respectively. The in vivo adsorption of Co and De conformed to the one-compartment model, with a longer time to attain the peak plasma concentrations. These results provided an experimental basis for revealing the active substance basis and clinical medication of Weichang'an pills.

Herein, we report an efficient approach for exploring the novel anticancer mechanism of (-)-ainsliatrimer A, a structurally complex and unique trimeric sesquiterpenoid, through a combined strategy of diverted total synthesis (DTS) and bioorthogonal ligation (TQ ligation), which allowed us to visualize the subcellular localization of this natural product in live cells. Further biochemical studies facilitated by pretarget imaging revealed that PPARγ, a nucleus receptor, was a functional cellular target of ainsliatrimer A. We also confirmed that the anticancer activity of ainsliatrimer A was caused by the activation of PPARγ., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A method based on high-performance liquid chromatography coupled with ultraviolet detection was developed for studying the pharmacokinetics of costunolide (Cos) and dehydrocostus lactone (Dehy) in rats after intravenous (i.v.) administration. Following i.v. administration, the maximum plasma concentrations of Cos and Dehy were observed to be 12.29 ± 1.47 and 5.79 ± 0.13 µg/mL, respectively. The bioavailability of Cos was larger than that of Dehy; however, the clearance and the volume of distribution of Dehy were much larger than those of Cos. An ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry system with automated MS(E) (E represents collision energy) data analysis software (MetaboLynx(TM)) was used to analyze and identify the metabolites of Cos and Dehy in vivo. Four metabolites of Cos and six metabolites of Dehy were discovered from the plasma, urine and feces of rats. The main metabolic pathway of Cos was phase II biotransformation, but the main metabolic pathways of Dehy was phase І biotransformation. Two sequential desaturations and N-acetylcysteine conjugation were the common metabolic pathways of Cos and Dehy in rats. This information may be useful for the further development of the two drug candidates., (Copyright © 2014 John Wiley & Sons, Ltd.)

A selective, sensitive, and accurate LC-MS/MS method for the simultaneous determination of isoalantolactone and alantolactone in rat plasma has been developed using psoralen as the internal standard. LC-MS/MS analysis was carried out on a Triple Quadrupole mass spectrometer using positive ion ESI and the selected reaction monitoring mode. The assays were linear in the range of 7.5-750 ng/mL for isoalantolactone and 5.5-550 ng/mL for alantolactone. The average recoveries in plasma samples both were better than 85%. The intra- and inter-day precision and accuracy values were found to be within the assay variability criteria limits according to the US FDA guidelines. The method was successfully applied to pharmacokinetic studies of the two structural isomers after an intravenous injection of Inula helenium formulation to rats., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Astragaloside IV, atractylenolide I, and prim-O-glucosylcimifugin are main medicinal components of the traditional Chinese medicine prescription Yu-ping-feng which is composed of three herbs: Astragalus membranaceus, Atractylodes macrocephala, and Saposhnikovia divaricata. This study is aimed to assess the influence of atractylenolide I and prim-O-glucosylcimifugin on the pharmacokinetic profile of astragaloside IV so as to investigate the pharmacokinetic mechanisms of the Yu-ping-feng prescription. Fifteen Sprague Dawley rats were randomized to three groups; astragaloside IV, astragaloside IV plus atractylenolide I, and a combination of astragaloside IV, atractylenolide I, and prim-O-glucosylcimifugin were respectively administered to rats of these three groups via intragastric gavage. Serum samples were collected at different times after drug administration, and serum concentrations of astragaloside IV and atractylenolide I were simultaneously detected using HPLC-electrospray ionization-MS. Compared with administration of astragaloside IV alone, concentrations of astragaloside IV in the serum were significantly increased when it was given in combination with atractylenolide I or atractylenolide I+prim-O-glucosylcimifugin, with higher values for Cmax (p = 0.019 and p = 0.033 compared with astragaloside IV + atractylenolide I and astragaloside IV + atractylenolide I + prim-O-glucosylcimifugin groups, respectively) and AUC (p = 0.0052 and p = 0.0047 compared with astragaloside IV + atractylenolide I and astragaloside IV + atractylenolide I + prim-O-glucosylcimifugin groups, respectively). Improvement in mean oral Cmax and mean systemic serum exposure because of the pharmacokinetic interaction between astragaloside IV and atractylenolide I might explain the rationale for the use of multiple herbs in Yu-ping-feng and of combinations of A.membranaceus and A. macrocephala., (Georg Thieme Verlag KG Stuttgart · New York.)

Ethnopharmacological Relevance: Radix Aucklandiae (RA), a well known traditional Chinese medicine, is widely used for treating various problems in digestive system. A selective and sensitive high-performance liquid chromatography coupled with mass spectrometry method was first developed and validated for simultaneous quantification of costunolide and dehydrocostuslactone in rat plasma with diazepam as internal standard after oral administration of RA extraction., Materials and Methods: Plasma samples were extracted via solid-phase extraction and detected by multiple-reaction monitoring mode under positive electrospray. Chromatographic separation was accomplished on an Agilent C18 column (2.1 mm × 150 mm, 5 µm), with 0.1% formic acid and acetonitrile (1:1) as the mobile phase at a flow rate of 0.5 mL/min., Results: The quantification was performed using the transitions of m/z 233/187 for costunolide, m/z 231/185 for dehydrocostuslactone and m/z 285/193 for diazepam, respectively. Calibration curves were linear over the concentration range of 0.7-769.7 ng/mL for costunolide and 0.9-956.0 ng/mL for dehydrocostuslactone. The intra-day and inter-day precisions (RSD%) for two compounds was less than 8.76% and 9.70% and the accuracy (RE%) range from 6.14% to 5.35%. The time to reach the maximum plasma concentration (Tmax) was 10.46 h for costunolide, 12.39 h dehydrocostuslactone. The elimination half-time (t1/2) of costunolide and dehydrocostuslactone was 5.54 ± 0.81 and 4.32 ± 0.71 (h). The AUC of costunolide and dehydrocostuslactone was 308.83 and 7884.51 respectively (ngh/mL)., Conclusions: It was the first report for the study of pharmacokinetic profile of costunolide and dehydrocostuslactone in rat plasma after oral administration of RA extract. These results provided a meaningful basis for better understanding the absorption of traditional medicine, RA, and provide useful scientific data for clinical application., (© 2013 Published by Elsevier Ireland Ltd.)

The drugs available for Chagas disease treatment are toxic and ineffective. We studied the in vivo activity of a new drug, lychnopholide (LYC). LYC was loaded in nanocapsules (NC), and its effects were compared to free LYC and benznidazole against Trypanosoma cruzi. Infected mice were treated in the acute phase at 2.0 mg/kg/day with free LYC, LYC-poly-ε-caprolactone NC (LYC-PCL), and LYC-poly(lactic acid)-co-polyethylene glycol NC (LYC-PLA-PEG) or at 50 mg/kg/day with benznidazole solution by the intravenous route. Animals infected with the CL strain, treated 24 h after infection for 10 days, evaluated by hemoculture, PCR, and enzyme-linked immunosorbent assay exhibited a 50% parasitological cure when treated with LYC-PCL NC and 100% cure when treated with benznidazole, but 100% of the animals treated during the prepatent period for 20 days with these formulations or LYC-PLA-PEG NC were cured. In animals with the Y strain treated 24 h after infection for 10 days, only mice treated by LYC-PCL NC were cured, but animals treated in the prepatent period for 20 days exhibited 100, 75, and 62.5% cure when treated with LYC-PLA-PEG NC, benznidazole, and LYC-PCL NC, respectively. Free LYC reduced the parasitemia and improved mice survival, but no mice were cured. LYC-loaded NC showed higher cure rates, reduced parasitemia, and increased survival when used in doses 2five times lower than those used for benznidazole. This study confirms that LYC is a potential new treatment for Chagas disease. Furthermore, the long-circulating property of PLA-PEG NC and its ability to improve LYC efficacy showed that this formulation is more effective in reaching the parasite in vivo.

The work presented here is the first study performed on the biotransformation and/or metabolism of atractylenolide I (1) as a valuable anti-inflammatory and chemopreventive agent, using liver microsomes from rats pre-treated with sodium phenobarbital. Two known eudesmane-type sesquiterpenoid lactones, namely 1β-acetoxyatractylenolide I (2) and 1β-hydroxy-atractylenolide I (3), and five new ones, namely 3β-hydroxy-atractylenolide I (4), 1β,13-dihydroxy-atractylenolide I (5), 1β,2α-dihydroxy-atractylenolide I (6), 1β,3α-dihydroxy-atractylenolide I (7), and 1β,3β-dihydroxy-atractylenolide I (8) were obtained. Their chemical structures were unambiguously established by both 1D and 2D NMR as well as mass spectroscopic techniques. The result indicated that the parent prototype compound 1 could be specifically oxidized at C-1, C-2 and C-3 of A-ring, suggesting that the oxidizable of 1 may contribute to its in vivo anti-inflammatory and chemopreventive effects. And the result also provided valuable information for further investigation of relationship among metabolic activation and liver microsomal cytochrome P450 enzyme isoforms., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Atractylenolide II (AII) and atractylenolide III (AIII) are the major active components in Atractylodes Macrocephala Rhizoma (AMR). In this study, a sensitive, rapid and selective liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of AII and AIII in rat plasma using loliolide as internal standard (IS). After protein precipitation with ethyl acetate, the analytes were injected into an LC-MS/MS system for quantification. Chromatography was performed using a C(18) column, eluting with water and acetonitrile (45:55, v/v) at 0.2 mL/min. All analytes including IS were monitored under positive ionization conditions by multiple reaction monitoring with an electrospray ionization source. The validated method was successfully applied to the pharmacokinetic study of AII and AIII in rat plasma after oral administration of AMR extract. The results provided a meaningful basis for evaluating the clinical applications of traditional Chinese medicine., (Copyright © 2012 John Wiley & Sons, Ltd.)

Objective: To study the stability of costunolide (COS) and dehydrocostus lactone (DEH) of Vladimiriae Radix before and after being roasted in artificial gastric juice, artificial intestinal juice and isolated rat gastric, intestinal or colonic incubation juice., Method: The HPLC method was used for the determination of the mass concentration of COS and DEH Vladimiriae Radix before and after being roasted artificial gastric juice, artificial intestinal juice and isolated rat gastric, intestinal or colonic incubation juice. The samples were incubated with isolated rat stomach, small intestine; colon was used to study physical adsorption, absorption or degradation parameters., Result: COS of Vladimiriae Radix before or after being roasted was unstable in artificial gastric juice, with the average degradation constants as 0.758 0 and 0.531 1. Having been roasted, it showed an increasing stability with a significant difference (P < 0.01). Both of COS and DEH of Vladimiriae Radix before or after being roasted showed high adsorption, uptake or degradation (2 h), and it had significant difference between different parts., Conclusion: COS was unstable in artificial gastric juice (unprocessed Vladimiriae Radix has a higher degradation rate). Isolated rat stomach, small intestine, colon can adsorb, take, degrade COS and DEH of Vladimiriae Radix before or after roasting process obviously and differently. It provides basis for studies on the absorption mechanisms of effective ingredients of Vladimiriae Radix before and after being roasted.

A new high-performance liquid chromatography/tandem mass spectrometry (LC-MS/MS) was developed for quantitative analysis of atractylenolide I in rat plasma using buspirone as internal standard (I.S.). Rat plasma samples were deproteined with methanol and acetonitrile (1:1, v/v). Atractylenolide I and I.S. were separated on a Phenomenex Gemini C(18) column (50 mm × 2.0 mm, 5 μm) with gradient mobile phase at the flow rate of 0.4 ml/min. The detection was performed by positive ion electrospray ionization (ESI) in multiple reaction monitoring (MRM) mode. The linear calibration curve of atractylenolide I in rat plasma ranged 2.0-5000 ng/ml (R>0.9979). The limit of detection (LOD) and the limit of quantification (LOQ) were 0.6 ng/ml and 2.0 ng/ml, respectively. Both accuracy and precision of the assay were satisfactory. The recoveries of atractylenolide I and I.S. were 91.4% and 87.8%, respectively. This fully validated method was applied to a pharmacokinetic study of atractylenolide I in rats administered with 20 g/kg Atractylodis extract. The main pharmacokinetic parameters T(max) (the time to peak), C(max) (the concentration to peak), T(0.5) (the biological half time), and K(e) (the elimination rate constant) were 0.81 ± 0.11h, 7.99 ± 1.2 ng/ml, 1.94 ± 0.27 h, 0.365 ± 0.06/h, respectively., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Costunolide and dehydrocostuslactone are well-known sesquiterpene lactones contained in many plants used as popular herbs, such as Saussurea lappa and Laurus novocanariensis, and have been considered as potential candidates for the treatment of various types of tumor. In the present work, a sensitive UPLC-MS/MS for the quantification of costunolide and dehydrocostuslactone in biological matrices has been developed. The method is based on protein precipitation with acetonitrile followed by isocratic ultraperformance liquid chromatographic separation using methanol-formic acid (0.1% in water; 70:30, v/v) mobile phase. Detection was performed by ESI mass spectrometry in MRM mode with the precursor-to-product ion transitions m/z 233-187 and m/z 231-185, respectively. The calibration curves of analytes showed good linearity within the established range 0.19-760  ng/mL for costunolide and 0.23-908  ng/mL for dehydrocostuslactone. The lower limits of quantification of costunolide and dehydrocostuslactone were found to be 0.19 and 0.23  ng/mL, respectively. The intra-day and inter-day presicions of this method for the entire validation were less than coefficient of variation of 7% and the accuracy was within ±8% (relative error). The mean extraction recoveries were 73.8 and 75.3%, respectively. The method was found to be precise, accurate and specific during the study, and was successfully used to analyze the pharmacokinetics of costunolide and dehydrocostuslactone., (Copyright © 2010 John Wiley & Sons, Ltd.)

Background: Multiple myeloma (MM) is a disease of cell cycle dysregulation while cell cycle modulation can be a target for MM therapy. In this study we investigated the effects and mechanisms of action of a sesquiterpene lactone 6-O-angeloylplenolin (6-OAP) on MM cells., Methodology/principal Findings: MM cells were exposed to 6-OAP and cell cycle distribution were analyzed. The role for cyclin B1 to play in 6-OAP-caused mitotic arrest was tested by specific siRNA analyses in U266 cells. MM.1S cells co-incubated with interleukin-6 (IL-6), insulin-like growth factor-I (IGF-I), or bone marrow stromal cells (BMSCs) were treated with 6-OAP. The effects of 6-OAP plus other drugs on MM.1S cells were evaluated. The in vivo therapeutic efficacy and pharmacokinetic features of 6-OAP were tested in nude mice bearing U266 cells and Sprague-Dawley rats, respectively. We found that 6-OAP suppressed the proliferation of dexamethasone-sensitive and dexamethasone-resistant cell lines and primary CD138+ MM cells. 6-OAP caused mitotic arrest, accompanied by activation of spindle assembly checkpoint and blockage of ubiquitiniation and subsequent proteasomal degradation of cyclin B1. Combined use of 6-OAP and bortezomib induced potentiated cytotoxicity with inactivation of ERK1/2 and activation of JNK1/2 and Casp-8/-3. 6-OAP overcame the protective effects of IL-6 and IGF-I on MM cells through inhibition of Jak2/Stat3 and Akt, respectively. 6-OAP inhibited BMSCs-facilitated MM cell expansion and TNF-α-induced NF-κB signal. Moreover, 6-OAP exhibited potent anti-MM activity in nude mice and favorable pharmacokinetics in rats., Conclusions/significance: These results indicate that 6-OAP is a new cell cycle inhibitor which shows therapeutic potentials for MM.

Objective: To investigate the absorption kinetics of atractylenolide I in intestines of rats and the influence of P-glycoprotein (P-gp) on the absorption., Method: The absorption kinetics was investigated using the method of in situ intestine absorption in rats and the samples were determined by HPLC., Result: Atractylenolide I is absorbed quite well at all segments of intestine in rats and no specific absorption was founded in different segment. When the concentration of perfusion solution was increased contrarily the absorption rate constant (Ka) kept at the same level. Compared Ka of three different concentration of perfusion solution with variance analysis method, Ka of atractylenolide I had no significant differences. But the Ka values were significently increased in the presence of P-gp inbibitor, verapamil or digoxin., Conclusion: Atractylenolide I can be classified into high penetrating drug. Passive diffusion dominates the absorptive transport behivior of atractylenolide I. Atractylenolide I can be absorbed in the whole intestinal segments and there is not a preferntial absorption zone in the intestine. The absorption and secretion of atractylenolide I are mediated by the efflux transport system, P-gp.

The aim of this paper is to investigate the characteristics of atractylenolide I (AO-I) in the body by a GC-MS method. All bio-samples were cleared up with a liquid-liquid extraction procedure. The calibration curves were linear within a range of 5-1000 ng/mL for plasma samples, 0.06-16.00 microg/g for cerebellum samples, and 0.03-8.00 microg/g for other tissue samples. The limit of quantification (LOQ) for AO-I was 1.0 ng/mL or 1.0 ng/g (S/N>micro=10) in the bio-samples. In the applications, the main pharmacokinetic parameters were firstly obtained as follows: Tmax=0.37+/-0.19 h, Cmax=0.26+/-0.05 microg/mL, AUC=1.95+/-0.30 microgh/mL and ka=10.08+/-5.60 h(-1). The tissue distribution of AO-I in rats after the oral administration of 50.0mg/kg was from 0.225 to 0.031microg/g with a decreasing tendency in different tissues like liver>kidney>spleen>cerebellum>heart>cerebrum>lung. The protein binding in rat plasma, human plasma and bovine serum albumin was 80.8+/-3.9, 90.6+/-3.1 and 60.9+/-5.1%, respectively.

A method for quantitative determination of atractylenolide II in rat plasma using reversed-phase high-performance liquid chromatography (RP-HPLC) coupled with UV spectrometry was established. From a variety of compounds and solvents tested, atractylenolide III was selected as the internal standard (IS) and ethyl acetate was found to be the best solvent for extracting atractylenolide II from plasma samples. RP-HPLC analysis of the extracts was performed on an analytical column (DIKMA ODS, 150 x 4.6 mm; i.d., 5 microm) equipped with a security guard pre-column system. There was good linearity over the range 0.05-5.0 microg/mL (r > 0.99). The recoveries were more than 90.0% in plasma, and the intra- and inter-day coefficients of variation were less than 10.0% in all cases. The limit of detection (LOD) was 0.025 microg/mL and the lower limit of quantification (LLOQ) was 0.05 microg/mL. The RP-HPLC method was applied to quantitate atractylenolide II in rat plasma within 24 h in a pharmacokinetics study where experimental rats received a single dose of atractylenolide II (60 mg/kg).

Objective: [corrected] To establish an HPLC method for the analysis of pharmacokinetics and tissue distribution of atractylenolide III in rats., Methods: The biological samples were extracted with ether. The chromatographic conditions were as follows: Hypersil ODS column (150 mm x 4.6 mm, 5 microm) was used. The mobile phase was methnol/warter (67 : 33) with a flow rate of 1.0 ml/min under the column temperature of 25 degrees C, and the detection wavelength was set at 220 nm., Results: The recovery of the method was 85.12% (RSD = 5.57%). The linear range was 0.2 microg/ml - 18.5 microg/ml (r = 0.9996) in rat plasma. The Lowest Limit of detection was 0.10 microg/ ml (S/N > 3). The within-day and between-day precision were from 0.98% to 6.19% and 12.95% to 15.48%, respectively. After oral administration of atractylenolide III (100 mg/kg), the concentration-time profiles of atractylenonlide III fit a two compartment model. In main effect tissues, the atractylenolide III concentration was followed as in order C(lung) > C(cerebellum) > C(heart) > C(cerebrum), and that was C(spleen) > C(liver) > C(kidney) in eliminated tissues., Conclusion: The method is accurate, stable and reliable, and can be used for the investigation of atractylenolide III in plasma and tissues of rats.

Atractylenolide III is a major active component in Atractylodes macrocephala. This paper describes a simple, rapid, specific and sensitive method for the quantification of atractylenolide III in rat plasma using a liquid-liquid extraction procedure followed by liquid chromatography mass spectrometric (LC-MS) analysis. A Kromasil 3.5 microm C(18) column (150 mm x 2.00 mm) was used as the analytical column. Linear detection responses were obtained for atractylenolide III concentration ranging from 5 to 500 ng L(-1). The precision and accuracy data, based on intra-day and inter-day variations over 5 days were within 10.29%. The lower limit of quantitation for atractylenolide III was 5 ng mL(-1), using 0.1 mL plasma for extraction and its recoveries were greater than 85% at the low, medium and high concentrations. The method has been successfully applied to a pharmacokinetic study in rats after an oral administration of atractylenolide III with a dose of 20.0 mg kg(-1). With the lower limits of quantification at 5 ng mL(-1) for atractylenolide III, this method was proved to be sensitive enough for the pharmacokinetics study of atractylenolide III.

Sesquiterpene lactones are terpenoid compounds characteristic of the Asteraceae (Compositae) possessing a variety of biological activities, such as cytotoxic, antitumor, antibacterial, and antifungal. The prediction of the pharmacokinetic profile of several antifungal sesquiterpene lactones, isolated from Greek taxa of Centaurea sp., was undertaken in this study using the VolSurf procedure. The molecules were projected on the following pre-calculated ADME models: Caco-2 cell permeability, plasma protein affinity, blood-brain barrier permeation and thermodynamic solubility. The in silico projection revealed a non optimal pharmacokinetic profile for the studied compounds. ADME in silico screening of a semi-synthetic derivatives virtual library has been performed in order to optimize the pharmacokinetic properties. A number of derivatives were proposed as it was predicted to have higher Caco-2 cell permeability, while the pharmacokinetic behaviour regarding BBB penetration, protein binding and solubility was mainly preserved.

Pharmacokinetics of the sesquiterpene lactone leucomisin in the blood serum was studied after single intraperitoneal injection and enteral introduction. Analysis of the main pharmacokinetic prameters shows that the drug circulates in the organism for a relatively long time and can be accumulated in the cells, probably, due to the ability of penetrating through the histohematic barriers.