The influence of essential oils from ZhaLi NuSi Prescription on the pharmacokinetics of its non-volatile components in normal rats.

Hui Medicine ZhaLi NuSi Prescription (ZLNS) is described in "Hui Hui Prescription," and it has been used to treat cerebral infarction in Hui Region, China. In this study, a rapid and reliable ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS/MS) method was established and applied to simultaneously determine geniposidic acid, oxypaeoniflorin, hydroxysafflor yellow A, caffeic acid, magnoflorine, paeoniflorin, ferulic acid, ß-ecdysterone, icariin, rhein, and baohuoside I in rat plasma. The pharmacokinetic parameters of these components and the influence of essential oils (EOs) on them were investigated in normal rats. The results showed that the pharmacokinetic parameters (AUC0 - t , AUC0 - ∞ , t1/2 , tmax , cmax ) of the aforementioned compounds were significantly changed after co-administering with ZLNS EO. The AUC values of oxypaeoniflorin, paeoniflorin, ferulic acid, and baohuoside I with EOs were decreased significantly. This is the first report for the comparative pharmacokinetic study of ZLNS bioactive components in normal rats, which may provide the basis for drug interaction study in vivo and insight into their clinical applications.

Intranasal administration of perillyl alcohol-loaded nanoemulsion and pharmacokinetic study of its metabolite perillic acid in plasma and brain of rats using ultra-performance liquid chromatography/tandem mass spectrometry.

Perillyl alcohol (POH) is a monocyclic terpene that has strong antitumor activity. Brain tumors are particularly difficult to treat with therapeutic agents, and clinical trials have shown their low tolerance through oral administration. We proposed the entrapment of POH into an oil-in-water chitosan nanoemulsion aiming its intranasal administration for brain targeting. An ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the quantitation of total metabolite perillic acid (PA) in plasma and brain of rats. The rat samples containing the metabolite were treated by liquid-liquid extraction with acetonitrile. The mobile phase was 0.1% formic acid in water (solvent A) and 0.1% formic acid in methanol (solvent B), at a flow rate of 0.3 mL min-1 in gradient elution. The chromatography was run for 10 min, and analytical curves were built in acetonitrile, plasma, and brain. The PA was detected in positive ion mode with multiple reaction monitoring. The method has shown high selectivity, sensitivity, and throughput. The low quantification limits of 162, 178, and 121 ng mL-1 for acetonitrile, brain, and plasma, respectively, indicate a good detectability of the method. The repeatability and precision observed were within the limits recommended in the literature. The accuracy of the method was verified through high recovery rates (106-118%). The validated method was successfully applied to the pharmacokinetic study of the metabolite PA after the intranasal administration of free or POH-loaded nanoemulsion in rats. The results showed that chitosan nanoemulsion improved the plasma and brain bioavailability of POH, representing a promising alternative to free POH treatment.

Pharmacokinetic-pharmacodynamic modeling analysis and anti-inflammatory effect of Wangbi capsule in the treatment of adjuvant-induced arthritis.

Clinically, Wangbi Capsule (WBC) is widely used in the treatment of Rheumatoid arthritis (RA) because of its remarkable therapeutic effect. To reveal the mechanism, a pharmacokinetic-pharmacodynamic (PK-PD) model was developed for the first time to assess the relationship between time-concentration (dose)-effect. Freund's Complete Adjuvant was used to induce the adjuvant-induced arthritis model. Multi-indices were used to evaluate the therapeutic effect and an S-Imax PK-PD model was established based on the concentrations of osthole, 5-O-methylvisamminoside, cimifugin, albiflorin, paeoniflorin and icariin and the levels of interleukin-1ß and prostaglandin E2 using a two-compartment PK model together with a PD model with an effect-site compartment. The results suggest that WBC can treat RA by regulating the levels of prostaglandin E2 and interleukin-1ß. For the PK-PD model, the parameters indicated that WBC had a large safety margin and all six bioactive ingredients of WBC have therapeutic effects on RA. Among them icariin, osthole and 5-O-methylvisamminoside may be the main effective substances. This study provided a scientific basis for further study of population pharmacokinetics / population pharmacodynamics (PPK/PPD), to develop a reasonable administration plan and improve individualized drug therapy.

Simultaneous determination of ferulic acid, paeoniflorin, and albiflorin in rat plasma by ultra-high performance liquid chromatography with tandem mass spectrometry: Application to a pharmacokinetic study of Danggui-Shaoyao-San.

A rapid, selective, and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry method was developed for simultaneous determination of ferulic acid, paeoniflorin, and albiflorin, the major active constituents of Danggui-Shaoyao-San, in rat plasma using geniposide as the internal standard. The plasma samples were processed by protein precipitation with acetonitrile, and then separated on a Shim-Pack XR-ODS C18 column (75 mm × 3.0 mm, 2.2 µm) using gradient elution program with a mobile phase consisting of 0.1% aqueous formic acid and acetonitrile at a flow rate of 0.4 mL/min. The detection was achieved on a 3200 QTRAP mass spectrometer equipped with electrospray ionization source in negative ionization mode. Quantification was performed using multiple reaction monitoring mode by monitoring the fragmentation of m/z 192.9→134.0 for ferulic acid, m/z 525.0→120.9 for paeoniflorin, m/z 525.2→121.0 for albiflorin, and m/z 433.1→225.1 for the internal standard, respectively. The calibration curve was linear in the range of 5-2500 ng/mL for all the three analytes (r ≥ 0.9972) with the lower limit of quantitation of 5 ng/mL. The intraday and interday precisions were below 12.1% for all the analytes in terms of relative standard deviation, and the accuracy was within ±11.5% in terms of relative error. The extraction recovery, matrix effect and stability were satisfactory in rat plasma. The validated method was successfully applied to a pharmacokinetic study of ferulic acid, paeoniflorin, and albiflorin after oral administration of Danggui-Shaoyao-San to rats.

UPLC-MS/MS simultaneous determination of seven active ingredients of Yaobitong capsule in rat plasma and its integrated pharmacokinetic application.

A reliable and sensitive UPLC-MS/MS method was first established and validated for the simultaneous determination of seven active ingredients of Yaobitong capsule in rat plasma: ginsenoside Rg1, ginsenoside Rb1, osthole, tetrahydropalmatine, paeoniflorin, albiflorin, and ferulic acid. And this method was further applied for the integrated pharmacokinetic study of Yaobitong capsule in rats after oral administration. Plasma samples (100 µL) were precipitated with 300 µL of methanol using carbamazepine as internal standard. Chromatographic separation was achieved using an Aquity UPLC BEH C18 column (100 × 2.1 mm, 1.7 µm), with the mobile phase consisting of 0.1% formic acid and acetonitrile. The method was validated using a good linear relationship (r ≥ 0.991), and the lower limit of quantification of the analytes ranged from 0.5 to 40 ng/mL. In the integrated pharmacokinetic study, the weight coefficient was calculated by the ratio of AUC0-∞ of each component to the total AUC0-∞ of the seven active ingredients. The integrated pharmacokinetic parameters Cmax , Tmax , and t1/2 were 81.54 ± 9.62 ng/mL, 1.00 ± 0.21 h, and 3.26 ± 1.14 h, respectively. The integration of pharmacokinetic parameters showed a shorter t1/2 because of fully considering the contribution of the characteristics of each active ingredient to the overall pharmacokinetics.

Comparative pharmacokinetics and metabolites study of seven major bioactive components of Shaoyao-Gancao decoction in normal and polycystic ovary syndrome rats by ultra high pressure liquid chromatography with tandem mass spectrometry.

A simple and sensitive liquid chromatography with tandem mass spectrometry method was developed for simultaneous quantification of paeoniflorin, albiflorin, oxypaeoniflorin, liquiritin, liquiritigenin, glycyrrhetinic acid, and glycyrrhizin in rat plasma after oral administration of Shaoyao-Gancao decoction, which is traditionally used in the treatment of polycystic ovary syndrome. The plasma samples were pretreated with methanol as precipitant. The method exhibited good linearity (correlation coefficient (R2 ) > 0.99) with lower quantification limits of 0.595-4.69 ng/mL for all analytes. Intra- and interbatch precision, accuracy, recovery, and stability of the method were all within accepted criteria. The results showed that the pharmacokinetic behaviors of the seven compounds were altered in the pathological status of polycystic ovary syndrome. Furthermore, a total of 36 metabolites were structurally identified based on their accurate masses and fragment ions. The major metabolic pathway involves phase I metabolic reactions (such as hydroxylation), phase II metabolic reactions (such as sulfation and glucuronidation conjugation) as well as the combined multiple-step metabolism. This study is the first report on the pharmacokinetic and metabolic information of Shaoyao-Gancao decoction in both normal and model rats, which would provide scientific evidences for the bioactive chemical basis of herbal medicines and also promote the clinical application of Shaoyao-Gancao decoction for treating polycystic ovary syndrome.

Effects of glycyrrhizin on the pharmacokinetics of paeoniflorin in rats and its potential mechanism.

Context: Paeoniflorin is reported to possess numerous pharmacological activities. Paeoniflorin and glycyrrhizin are always used together for the treatment of disease in China clinics; however, the drug-drug interaction between glycyrrhizin and paeoniflorin is still unknown. Objective: This study investigates the effects of glycyrrhizin on the pharmacokinetics of paeoniflorin in rats. Materials and methods: The pharmacokinetics of orally administered paeoniflorin (20 mg/kg) with or without glycyrrhizin pre-treatment (at a dose of 100 mg/kg/day for 7 days) were investigated in male Sprague-Dawley rats using LC-MS/MS. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism. Results: The results showed that when the rats were pre-treated with glycyrrhizin, the Cmax of paeoniflorin decreased from 59.57 ± 10.24 to 45.36 ± 8.61 ng/mL, and AUC0-inf also decreased from 282.02 ± 35.06 to 202.29 ± 28.28 µg·h/L. The t1/2 value of paeoniflorin decreased from 8.48 ± 2.01 to 5.88 ± 1.15 h (p < 0.05). The Caco-2 cell transwell experiments indicated that glycyrrhizin could increase the efflux ratio of paeoniflorin from 2.71 to 3.52, and the rat liver microsome incubation experiments showed that glycyrrhizin could significantly increase its intrinsic clearance rate from 53.7 ± 4.6 to 85.6 ± 7.1 µL/min/mg protein. Conclusions: These results indicated that glycyrrhizin could affect the pharmacokinetics of paeoniflorin, and it might work through decreasing the absorption of paeoniflorin by inducing the activity of P-gp or through increasing the clearance rate in rat liver by inducing the activity of CYP450 enzyme.

R-Limonene metabolism in humans and metabolite kinetics after oral administration.

We studied the R-limonene (LMN) metabolism and elimination kinetics in a human in vivo study. Four volunteers were orally exposed to a single LMN dose of 100-130 µg kg-1 bw. In each case, one pre-exposure and subsequently all 24 h post-exposure urine samples were collected. From two subjects, blood samples were drawn up to 5 h after exposure. The parent compound was analysed in blood using headspace GC-MS. The metabolites cis- and trans-carveol (cCAR), perillyl alcohol (POH), perillic acid (PA), limonene-1,2-diol (LMN-1,2-OH), and limonene-8,9-diol (LMN-8,9-OH) were quantified in both blood and urine using GC-PCI-MS/MS. Moreover, GC-PCI-MS full-scan experiments were applied for identification of unknown metabolites in urine. In both matrices, metabolites reached maximum concentrations 1-2 h post-exposure followed by rapid elimination with half-lives of 0.7-2.5 h. In relation to the other metabolites, LMN-1,2-OH was eliminated slowest. Nonetheless, overall renal metabolite elimination was completed within the 24-h observation period. The metabolite amounts excreted via urine corresponded to 0.2 % (cCAR), 0.2 % (tCAR), <0.1 % (POH), 2.0 % (PA), 4.3 % (LMN-1,2-OH), and 32 % (LMN-8,9-OH) of the orally administered dose. GC-PCI-MS full-scan analyses revealed dihydroperillic acid (DHPA) as an additional LMN metabolite. DHPA was estimated to account for 5 % of the orally administered dose. The study revealed that human LMN metabolism proceeds fast and is characterised by oxidation mainly of the exo-cyclic double bond but also of the endo-cyclic double bond and of the methyl side chain. The study results may support the prediction of the metabolism of other terpenes or comparable chemical structures.

Human metabolism of α-pinene and metabolite kinetics after oral administration.

We studied the human in vivo metabolism and the elimination kinetics of α-pinene (αPN), a natural monoterpene which commonly occurs in the environment. Four volunteers were exposed to a single oral dose of 10 mg αPN. Each subject provided one pre-exposure and subsequently all post-exposure urine samples up to 24 h after administration. Additionally, blood samples were drawn hourly from two volunteers for 5 h. The analysis of the parent compound in blood was performed by a headspace GC-MS procedure, whereas the proposed αPN metabolites myrtenol (MYR) and cis- and trans-verbenol (cVER; tVER) were quantified in blood and urine using GC-PCI-MS/MS. Unknown metabolites were investigated using GC-PCI-MS full-scan analyses. The urinary concentration of the metabolites reached their maxima 1.6 h after exposure. Afterwards, they declined to the pre-exposure levels within the 24-h observation period with elimination half-lives of 1.5 h (MYR) and 1.6 h (cVER and tVER). The total eliminated amounts corresponded to 1.5 % (MYR), 5.6 % (cVER), and 4.1 % (tVER) of the orally applied dose. The GC-PCI-MS full-scan analyses identified three novel metabolites, of which one conforms to myrtenic acid (MYRA). A re-analysis of MYRA in urine showed maximum elimination 1.6 h after αPN ingestion, an elimination half-life of 1.4 h, and a share of the oral dose of 6.7 %. The study revealed that the human in vivo metabolism of αPN proceeds fast and elimination of metabolites takes places rapidly. The metabolism of αPN is dominated by extensive oxidation reactions at the methyl side-chains yielding in carboxylic acid structures as well as by allylic oxidation of the cyclohexenyl backbone, whereas predicted products of a double-bond oxidation were not detected.

Simultaneous determination of ginsenoside Rb1, ginsenoside Rg1, paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma by liquid chromatography-tandem mass spectrometry: Application to a pharmacokinetic study of wen-Yang-Huo-Xue soft capsule.

A simple and sensitive HPLC-MS/MS method was developed and fully validated for simultaneous determination of ginsenoside Rb1, ginsenoside Rg1, paeoniflorin, albiflorin and oxypaeoniflorin in rat plasma. Plasma samples were pretreated with protein precipitation using acetonitrile. The chromatographic separation was carried out on a C18 column with a gradient mobile phase consisting of acetonitrile and water (containing 0.1% formic acid). All analytes and digoxin (internal stand, IS) were quantitated through electrospray ionization in negative ion multiple reaction monitoring mode. All calibration curves exhibited good linearity (r > 0.9960) over a wide concentration range for all components. The intra-day and inter-day precisions (RSD) at three different levels were all <12.0% and the accuracies (RE) ranging from -6.1 to 6.2%. The extraction recoveries of the five compounds ranged from 89.2 to 97.1%. The validated method was successfully applied in a comparative pharmacokinetic study of Wen-Yang-Huo-Xue soft capsule (WYHXSC) in rats. Compared with single pure component, the exposure of the investigated components, except for oxypaeoniflorin, increased after oral administration of WYHXSC in rats, which suggested a synergistic effects between the herbs in the WYHXSC preparations.

Simultaneous determination of wogonin, oroxylin a, schisandrin, paeoniflorin and emodin in rat serum by HPLC-MS/MS and application to pharmacokinetic studies.

Wogonin and oroxylin A in Scutellariae Radix, schisandrin in Chinensis Fructus, paeoniflorin in Moutan Cortex and emodin in Polygoni Cuspidate Rhizome et Radix are anti-inflammatory active compounds. A method for simultaneous determination of the five compounds in rat was developed and validated using high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS). The separation was performed on a Symmetry C18 column (4.6 × 50 mm, 3.5 µm) with acetonitrile and 0.1% formic acid aqueous solution as the mobile phases. The detection was performed using multiple-reaction monitoring with electrospray ionization source in positive-negative ion mode. The calibration curves showed good linearity (r ≥ 0.9955). The lower limit of quantification (LLOQ) was 5 ng/mL for wogonin and schisandrin, 10 ng/mL for oroxylin A and emodin, and 15 ng/mL for paeoniflorin, respectively. The relative standard deviations of intraday and interday precisions were <11.49 and 14.28%, respectively. The extraction recoveries and matrix effects were acceptable. The analytes were stable under the experiment conditions. The validated method has been successfully applied to pharmacokinetic studies of the five compounds in rats after oral administration of Hu-gan-kan-kang-yuan capsule. This paper would be a valuable reference for pharmacokinetic studies of Chinese medicine preparations containing the five compounds.

Pharmacokinetics and disposition of monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) after intravenous dosing of antiseptic XueBiJing injection in human subjects and rats.

AIM: Monoterpene glycosides derived from Paeonia lactiflora roots (Chishao) are believed to be pharmacologically important for the antiseptic herbal injection XueBiJing. This study was designed to characterize the pharmacokinetics and disposition of monoterpene glycosides. METHODS: Systemic exposure to Chishao monoterpene glycosides was assessed in human subjects receiving an intravenous infusion and multiple infusions of XueBiJing injection, followed by assessment of the pharmacokinetics of the major circulating compounds. Supportive rat studies were also performed. Membrane permeability and plasma-protein binding were assessed in vitro. RESULTS: A total of 18 monoterpene glycosides were detected in XueBiJing injection (content levels, 0.001-2.47 mmol/L), and paeoniflorin accounted for 85.5% of the total dose of monoterpene glycosides detected. In human subjects, unchanged paeoniflorin exhibited considerable levels of systemic exposure with elimination half-lives of 1.2-1.3 h; no significant metabolite was detected. Oxypaeoniflorin and albiflorin exhibited low exposure levels, and the remaining minor monoterpene glycosides were negligible or undetected. Glomerular-filtration-based renal excretion was the major elimination pathway of paeoniflorin, which was poorly bound to plasma protein. In rats, the systemic exposure level of paeoniflorin increased proportionally as the dose was increased. Rat lung, heart, and liver exposure levels of paeoniflorin were lower than the plasma level, with the exception of the kidney level, which was 4.3-fold greater than the plasma level; brain penetration was limited by the poor membrane permeability. CONCLUSION: Due to its significant systemic exposure and appropriate pharmacokinetic profile, as well as previously reported antiseptic properties, paeoniflorin is a promising XueBiJing constituent of therapeutic importance.

Simultaneous determination of paeoniflorin from total glucosides of paeony in Sprague-Dawley rats and spontaneously hypertensive rats by high-performance liquid chromatography-tandem mass spectrometry: in vivo and in vitro studies.

Paeoniflorin is a well-known monoterpene glucoside in the herbal drug that exhibits a number of biological activities. The pharmacokinetic characteristics of paeoniflorin from total glucosides of paeony in spontaneously hypertensive rats (SHR) are still unclear. It is essential to investigate the in vivo and in vitro pharmacokinetic differences of paeoniflorin from total glucosides of paeony in Sprague-Dawley (SD) and SHR. The in vivo pharmacokinetic data were analyzed using DAS 2.0 software and the in vitro metabolic characteristics were measured using rat hepatic microsomes. The concentration of paeoniflorin in biological samples was determined using high-performance liquid chromatography-electrospray ionization tandem mass spectrometry method, which showed good precision and stability. The plasma concentration-time profiles of paeoniflorin following oral administration of total glucosides of paeony showed a single peak and there were significant differences in the mean values of AUC(0-t) , AUC(0-∞) , CLz /F and Tmax between SD and SHR (p < 0.05). The metabolic rate of paeoniflorin from total glucosides of paeony was slower in SHR than in SD rats (p < 0.05). The results might be useful in further applications of paeoniflorin and total glucosides of paeony. Copyright © 2016 John Wiley & Sons, Ltd.

Preparation, characterization and pharmacokinetic studies of linalool-loaded nanostructured lipid carriers.

Context Linalool (LL) is associated with numerous pharmacological activities. However, its poor solubility usually results in poor bioavailability, and further limited its applications. Objective To reduce volatilization and improve bioavailability of LL, linalool-loaded nanostructured lipid carriers (LL-NLCs) were prepared. Materials and methods LL-NLCs were prepared using high-pressure homogenization method and optimized via response surface methodology-central composite design, followed by characterization, including particle size (PS), zeta potential (ZP), transmission electron microscope (TEM), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and in vitro release study. Rats were administered 300 mg × kg (-) (1) LL with each preparation (LL-NLCs or LL) via oral gavage. Results LL-NLCs had a PS of 52.72 nm with polydispersity index of 0.172, and ZP of -16.0 mV. The encapsulation efficiency and drug loading gave 79.563 and 7.555%, respectively. The cumulative release of LL from free LL reached 51.414% at 180 min, while LL from LL-NLCs was 15.564%. All the pharmacokinetics parameters of LL-NLCs were better than those of LL, including Cmax (from 1915.45 to 2182.45 ng × mL (-) (1)), AUC0-t (from 76003.40 to 298948.46 ng × min × mL (-) (1)) and relative bioavailability (393.34%). The t1/2, MRT and tmax of LL-NLCs (110.50, 146.66 and 60 min) were also longer than that of LL (44.72, 45.66 and 40 min). Discussion and conclusion LL-NLCs were for the first time prepared and its oral administration in rats thoroughly investigated. LL-NLCs exhibited sustained release effect and increased absorption of LL. Therefore, these findings might provide a potential possibility for clinical application of LL.

Evaluation of the influence of sulfur fumigation on the pharmacokinetics of four active ingredients in Si Wu Tang.

Sulfur fumigation may induce the decrease or the chemical transformation of some active ingredients of traditional Chinese medicines in vitro. Whether sulfur fumigation can cause the pharmacokinetic changes of the active ingredients in vivo is related to the efficacy and the safety of Chinese medicines' application clinically. A sensitive, specific, and accurate method for the simultaneous determination of paeoniflorin, ferulic acid, senkyunolide A, and senkyunolide I in rat plasma by ultra high performance liquid chromatography coupled with triple quadrupole mass spectrometry was developed to evaluate the influence of sulfur fumigation to Si Wu Tang for the first time. Each compound was extracted from plasma samples by liquid-liquid extraction with ethyl acetate, and the chromatographic separation was accomplished on an Agilent Extend C18 column with a linear gradient elution. The mass spectrometric detection and analysis were performed by using an AB Sciex triple quadrupole 5500 mass spectrometer in multiple reaction monitoring mode. The validated method was successfully applied to a pharmacokinetic study of four compounds in rats after oral administration of sun-dried and sulfur-fumigated Si Wu Tang. The results provided a meaningful basis for evaluating the affection of sulfur fumigation to the clinical application and the efficacy of Si Wu Tang.

Development and validation of UHPLC-MS/MS assay for rapid determination of a carvone Schiff base of isoniazid (CSB-INH) in rat plasma: application to pharmacokinetic study.

In this study, a fast UHPLC-MS/MS method was developed and validated for the determination of a novel potent carvone Schiff base of isoniazid (CSB-INH) in rat plasma using carbamazepine as an internal standard (IS). After a single-step protein precipitation by acetonitrile, CSB-INH and IS were separated on an Acquity BEH(TM) C18 column (50 × 2.1 mm, 1.7 µm) under an isocratic mobile phase, consisting of acetonitrile: 10 mM ammonium acetate (95:5, v/v), at a flow rate of 0.3 mL/min. Quantification was performed on a triple quadrupole tandem mass spectrometer in multiple reactions monitoring mode by using positive electrospray ionization source. The precursor to product ion transitions were set at m/z 270.08 → 79.93 for CSB-INH and m/z 237.00 → 178.97 for IS. The proposed method was validated in compliance with US Food and Drug Administration and European Medicines Agency guidelines for bioanalytical method validation. The method was found to be linear in the range of 0.35-2500 ng/mL (r(2) ≥ 0.997) with a lower limit of quantification of 0.35 ng/mL. The intra- and inter-day precision values were ≤12.0% whereas accuracy values ranged from 92.3 to 108.7%. In addition, other validation results were within the acceptance criteria and the method was successfully applied in a pharmacokinetic study of CSB-INH in rats.

Simultaneous determination of ascaridole, p-cymene and α-terpinene in rat plasma after oral administration of Chenopodium ambrosioides L. by GC-MS.

A sensitive and reliable GC-MS method was developed and validated for the simultaneous determination of ascaridole, p-cymene and α-terpinene in rat plasma using naphthalene as internal standard. The plasma samples were extracted with ethyl acetate. Chromatographic separation was carried out on a HP-5MS capillary analytical column (30 m × 0.25 mm, 0.25 µm) and detection was performed on a quadrupole mass spectrometer detector operated under selected ion monitoring mode. The method showed excellent linearity over the investigated concentration range (r > 0.99) with the limit of quantitation down to 50, 10 and 5 ng/mL for ascaridole, p-cymene and α-terpinene, respectively. The intra-day and inter-day precisions (RSD) were <11.3%, and the accuracy was between 90.7 and 113.8%. The method was successfully applied to investigate the pharmacokinetics of Chenopodium ambrosioides L. following oral administration to rats.

Pharmacokinetic comparisons by UPLC-MS/MS of isomer paeoniflorin and albiflorin after oral administration decoctions of single-herb Radix Paeoniae Alba and Zengmian Yiliu prescription to rats.

Zengmian Yiliu (ZMYL), a traditional Chinese formula, is designed to improve clinical efficacy and reduce adverse effects in combination with cisplatin in ovarian cancer chemotherapy. In ZMYL, Radix Paeoniae Alba (RPA, made from root of Paeonia lactiflora Pall.) acts as an adjunctive drug in cancer treatment by ameliorating side effects induced by radio- and chemotherapy. The pharmacokinetics differences between isomer albiflorin and paeoniflorin, the main components of RPA, after oral administration decoction of single-herb RPA and ZMYL were compared using a sensitive and accurate UPLC-MS/MS. The results indicate that there are statistically significant differences between the pharmacokinetic parameters: decreasing area under the plasma concentration-time curve (AUC), maximum concentration (Cmax ), elimination rate constant (Ke ) and increasing apparent volume of distribution (Vd ) and clearance (CL) for albiflorin, increasing distribution half-life (T1/2d ) and decreasing elimination half-life (T1/2e ), distribution rate constant (Kd ) and absorption rate constant (Ka ) for paeoniflorin in the ZMYL group compared with the single-herb RPA group. In comparison with albiflorin, the pharmacokinetic parameters of paeoniflorin included significantly increasing mean residence time (MRT) and Vd , decreasing CL and Ke in the single-herb RPA group and increasing MRT and T1/2d and decreasing CL, Ke and Kd in the ZMYL group. Both paeoniflorin and albiflorin are more likely, as the main active ingredients in RPA and ZMYL, to play a variety of pharmacological effects, and herb-herb interactions occur, resulting in different pharmacokinetics of albiflorin and paeoniflorin in RPA and ZMYL.

Comparisons of the pharmacokinetic profile of four bioactive components after oral administration of gan-sui-ban-xia decoction plus-minus gansui and gancao drug combination in normal rats.

Gan-Sui-Ban-Xia Decoction (GSBXD) was first presented by Zhang Zhongjing in the book Synopsis of Golden Chamber during the Han Dynasty period. The formula was then used for the treatment of persistent fluid retention with floating pulse in Traditional Chinese Medicine (TCM), which in modern medicine is known as malignant ascites. Here, a rapid liquid chromatography-tandem mass spectrometry (LC-MS/MS) method has been developed for the determination of glycyrrhizinic acid, liquiritin, paeoniflorin, albiflorin after oral administration of GSBXD plus-minus Gansui and Gancao anti-drug combination to investigate the possible pharmacokinetic profile differences of different prescriptions with GSBXD in normal rats. The differences of pharmacokinetic parameters among groups were tested by the Student's t-test with p < 0.05 as the level of significance. Significant differences were found between the Gansui and Gancao anti-drug combination and other herbs in GSBXD on pharmacokinetic profile of glycyrrhizinic acid, liquiritin, paeoniflorin and albiflorin. The obtained knowledge might contribute to the rationality of the clinic use of GSBXD and also reveal the compatibility conditions of the Gansui and Gancao anti-drug combination.

Antitumorigenic potential of linalool is accompanied by modulation of oxidative stress: an in vivo study in sarcoma-180 solid tumor model.

Coriander, used as a common food seasoning, contains linalool as the main constituent of its essential oil. In this study, we tested the effect of linalool vis-à-vis that of a conventional chemotherapeutic drug, cyclophosphamide, against solid S-180 tumor-bearing Swiss albino mice. Tumor volume, cell count, cell cycle phase distribution, apoptosis, and proliferation markers indicate that linalool has potent antitumor activity. In vitro and in vivo data suggest that induction of oxidative stress might be responsible for the anticancer effect of linalool. However, interestingly, unlike cyclophosphamide, linalool did not induce myelosuppression or hepatotoxicity in mice as evident from bone marrow cell count, status of hepatic oxidative stress/antioxidant enzymes, and histopathology. Thus, linalool exerted prooxidant effect in tumor tissue and an antioxidant effect in liver. This is also supported by the expression of Nrf-2 and p21, which are considered to be important players in response to oxidative stress. Moreover, administration of linalool modulated the proliferation of spleen cells in tumor-bearing mice challenged with lipopolysaccharide. Finally, the detection of linalool in sera and tumor tissues by HPLC confirmed its bioavailability. In conclusion, linalool showed differential cytotoxicity towards tumor and normal cells in contrast to cyclophosphamide, which is uniformly toxic to both.