Pharmacokinetic properties of isorhamnetin, kaempferol and quercetin after oral gavage of total flavones of Hippophae rhamnoides L. in rats using a UPLC-MS method

An ultra performance liquid chromatography-mass spectrometric (UPLC-MS) method was developed to investigate the pharmacokinetic properties of isorhamnetin, kaempferol and quercetin from a total flavone extract of Hippophae rhamnoides L. (TFH) after single dose oral administration. Rat plasma samples were pretreated using liquid-liquid extraction, and chromatographic separation was performed on a C₁₈ column using a linear gradient of methanol and formic acid (0.1%). The pharmacokinetic parameters of isorhamnetin, kaempferol and quercetin from TFH in rats were quantitatively determined by UPLC with photodiode array detection (PDA). The qualitative detection of the three flavones was accomplished by selected ion monitoring in negative ion mode ESI-MS. Results of the pharmacokinetic study indicate that the three flavones in TFH were absorbed by passive diffusion in rats, and no “double-peak” phenomenon was observed in C-t curves of the three flavones from TFH except for quercetin. Results of this study indicate that the pharmacokinetic behaviors of isorhamnetin, kaempferol and quercetin when administered together in a complex herbal extract might be different than the individual behaviors of the same compounds administered in their pure forms. Results of this study also demonstrate that UPLC-MS is a rapid and practical method to determine the pharmacokinetic parameters of flavones present in an herbal extract.     

Comparative pharmacokinetics of paclitaxel after oral administration of Taxus yunnanensis extract and pure paclitaxel to rats

Taxus yunnanensis (T. yunnanensis) is endemic to China and has been used in traditional medicine for the treatment of cancer, diabetic ailments and others. Paclitaxel is a representative antitumor compound in the Taxus species. The pharmacokinetic behavior of paclitaxel after oral administration of the crude extract of T. yunnanensis has not been investigated. This study attempts to compare the pharmacokinetics of paclitaxel after an oral administration of the crude extract of the twigs and leaves of T. yunnanensis and pure paclitaxel. A UPLC and a UPLC/MS/MS analysis method were developed for the determination of paclitaxel in T. yunnanensis extract and in the comparative pharmacokinetic study. Caco-2 cells were used to investigate the transport profile of paclitaxel in vitro. In the pharmacokinetic study, rats were randomly grouped and administered with T. yunnanensis extract or pure paclitaxel. The results showed that the AUC and C_max of paclitaxel in rats receiving the T. yunnanensis extract were significantly increased than those receiving the pure paclitaxel, and the in vitro Caco-2 cell monolayer transport study found that the coexisting constituents in the extract of T. yunnanensis could inhibit the efflux of paclitaxel. These findings suggested that the oral absorption and bioavailability of paclitaxel in T. yunnanensis extract were remarkably higher when compared with the pure paclitaxel, and the coexisting constituents in the T. yunnanensis extract might play an important role for the enhancement of the oral absorption and bioavailability of paclitaxel.     

Comparative pharmacokinetics of three triterpene acids in rat plasma after oral administration of Poria extract and its formulated herbal preparation: GuiZhi-FuLing capsule

A sensitive liquid chromatographic-mass spectrometric technique coupled with liquid-liquid extraction method was developed and validated for simultaneous determination of dehydro-tumulosic acid, tumulosic acid and polyporic acid C in rat plasma. The analytes were separated on a Kromasil C₁₈ column with a total running time of 12.5 min. Author had compared the pharmacokinetics of dehydro-tumulosic acid, tumulosic acid and polyporic acid C after oral administration of the extract of Poria and its formulated herbal preparation (GuiZhi-FuLing capsule). The improved pharmacokinetic profiles of the three compounds were found in the GuiZhi-FuLing capsule, indicating the more effective absorption and the slower elimination, compared with the Poria extract. Furthermore, this study revealed that as far as the Poria extract was concerned, it is very valuable to be used as a clinical instruction of GF capsule.     

Comparative pharmacokinetic profiles of picrosides I and II from kutkin,Picrorhiza kurroa extract and its formulation in rats

Picrosides I and II are the active chemical constituents, present in the roots and rhizomes of Picrorhiza kurroa Royle (family: Scrophulariaceae). The plant is ethnomedically claimed for the treatment of liver and upper respiratory tract infection, fever, dyspepsia and scorpion sting. This study attempts to determine the in vivo pharmacokinetic profile of picrosides I and II in rats after oral administration of three different preparations namely, kutkin (a mixture of picrosides I and II), P. kurroa extract and Picrolax® capsule (marketed formulation). A simple, precise, specific and sensitive method was developed for simultaneous quantification of picrosides I and II in rat plasma and was applied for the pharmacokinetic study. Pharmacokinetic parameters were calculated from the observed plasma concentration of picrosides I and II. The results showed a significant difference (p ≤ 0.05) in oral bioavailability of picrosides I and II from different preparations. Both the compounds were found to be more bioavailable from P. kurroa extract followed by Picrolax® capsule and kutkin. Moreover, we also developed a novel method for isolation of kutkin from roots of P. kurroa with a high yield of 2.4% w/w. The information gained from this study provides a meaningful basis for clinical application and mechanistic study of such phytochemicals.     

Comparative pharmacokinetics and bioavailability studies of quercetin, kaempferol and isorhamnetin after oral administration of Ginkgo biloba extracts, Ginkgo biloba extract phospholipid complexes and Ginkgo biloba extract solid dispersions in rats

The aim of this study was to improve the oral bioavailability of Ginkgo biloba extract (GBE) through preparing G. biloba extract phospholipid complexes (GBP) and G. biloba extract solid dispersions (GBS). Firstly we prepared the GBP and GBS and studied their physicochemical properties by differential scanning calorimetry (DSC), powder X-ray diffraction (XRD) and dissolution. Then we studied the pharmacokinetic characteristics and bioavailability in rats. The results showed that the bioavailability of quercetin, kaempferol and isorhamnetin in rats was increased remarkably after oral administration of GBP and GBS comparing with GBE. The bioavailabilities of GBP increased more than that of GBS.     

Formulation and pharmacokinetic evaluation of hard gelatin capsule encapsulating lyophilized Vasa Swaras for improved stability and oral bioavailability of vasicine

The oral bioavailability of vasicine (1) was investigated in hard gelatin capsules of lyophilized Vasa Swaras (aqueous extract of Adhatoda vasica Nees.,Fam.: Acanthaceae) The rat pharmacokinetic profile of lyophilized Vasa Swaras, Vasa Swaras, vasicine (1) (chief marker compounds of A. vasica) and a marketed capsule formulation of A. vasica were compared. Vasicine (1) was found to be more orally bioavailable from lyophilized Vasa Swaras, with an overall minor conversion to vasicinone (2).     

Bioactivities of caffeic acid methyl ester (methyl-(E)-3-(3,4-dihydroxyphenyl)prop-2-enoate): a hydroxycinnamic acid derivative from Solanum melongena L. fruits

Feeding deterrent and growth inhibitory effects of caffeic acid methyl ester (CME) isolated from the fruit extract of eggplant, Solanum melongena L. along with two known phenolic acids, caffeic acid (CA) and chlorogenic acid (CG) and azadirachtin (taken as active control), were evaluated against Spodoptera litura Fab. and Achaea janata L. (Lep., Noctuidae). The structure of CME was determined on the basis of extensive spectroscopic (UV, FTIR, ¹H, and ¹³C NMR) data analysis. CME has exhibited strong feeding deterrent activity against S. litura and A. janata larvae with ED₅₀ values of 52.02 and 41.02 μg/cm² leaf area, respectively. CA and CG were relatively less effective compounds when compared with CME. The results also revealed that the isolated compound CME caused marked larval growth inhibition in S. litura and A. janata larvae after 7 days of feeding on a treated diet. The effect on growth of larvae was concomitant with the reduced feeding and digestibility of ingested food. So the activities of digestive proteases within the midgut of larvae were examined using specific substrates to understand the digestive physiology in the larval guts. The bulk of the activity was associated with serine proteases comprising trypsin-, chymotrypsin-, and elastase-like enzymes, which decreased in diets containing CME, whereas, interestingly increased with CG. From the results, we conclude that CME isolated from S. melongena fruit extract shows feeding deterrent and larval development inhibitory activities that may prove useful in the management of S. litura and A. janata larvae.     

Furostanol saponins from the seeds of Allium cepa L.

Allium cepa L. is one of the most widely cultivated and used plants. In addition to its bulb (onion), which is used as food in many cultures, the seeds of A. cepa L. are used as a traditional herbal medicine by the Uygur nationality in China to treat diarrhea and promote blood flow. In a bioactivity-screening, the ethanol extract of seeds of A. cepa L. showed inhibitory effects on protein tyrosine phosphatase 1B (PTP1B) enzyme, with 81.1% inhibition. Phytochemical investigation of the ethanol extract of red onion (Allium cepa L.) seeds led to the isolation of eight new furostanol saponins, named ceparosides E–L (1–8). Their structures were established using 1D and 2D NMR spectroscopy, mass spectrometry and chemical methods. Compounds 1–8 were screened for inhibitory effects on the PTP1B enzyme and cytotoxic activity against five human cells, including HCT-8, Bel-7402, BGC-823, A549 and A2780, but all were found to be inactive.     

The use of PEGylated liposomes to prolong the circulation lifetime of salvianolic acid B

The clinical application of salvianolic acid B (Sal B), a potential therapeutic agent for cardiovascular diseases isolated from Salvia miltiorrhiza, is greatly restricted by its short half-life and low bioavailability. To improve therapeutic effects and prolong the systemic circulation time of Sal B, liposomes, composed of soybean phosphatidylcholine and cholesterol were prepared by reverse-phase evaporation method. In addition, polyethylene glycol 2000-disteroylphosphoethanolamine (PEG-DSPE 2000) was included to give steric barrier to liposomes. A central composite design was employed to optimize liposomal formulation with high encapsulation efficiency and small particle size. Physicochemical characteristics such as particle size, zeta potential, encapsulation efficiency and in vitro release were investigated. In vivo pharmacokinetic properties of Sal B in beagle dogs and the effect of PEG on the blood circulation time of Sal B-loaded liposomes were also evaluated. An optimized formulation with encapsulation efficiency of 73.68% and mean particle size of 136.6nm were developed. Encapsulation of Sal B into conventional and PEGylated liposomes could prolong the half-life of Sal B by 5.8- and 17.5-fold and enhance the AUC(0-t) of Sal B by 6.7- and 13.3-fold compared with free Sal B, respectively. Therefore, the use of PEGylated liposomes could prolong the circulation time in blood and longevity effect of liposomes on Sal B was increased by PEG.     

Salvianolic acids T and U: A pair of atropisomeric trimeric caffeic acids derivatives from root of Salvia miltiorrhiza

Two new trimeric caffeic acids, named salvianolic acids T and U (1 and 2), were isolated from the underground part of Salvia miltiorrhiza. Their structures, consisting of three caffeic acid units, were determined based on extensive 1D- and 2D-spectroscopic analyses and electronic circular dichroism (ECD) calculations.     

Effects of a bio-assay guided fraction from Polygonum cuspidatum root on the viability,acid production and glucosyltranferase of mutans streptococci

Polygonum cuspidatum root has been traditionally used for the treatment of dental diseases in Korea. The purpose of this study was to evaluate effects of P. cuspidatum root on the development of dental caries, especially its effects against bacterial viability and caries-inducing factors of Strptococcus mutans and Strptococcus sobrinus. Among methanol extract of P. cuspidatum root and its fraction tested, ethyl acetate fraction, composed of polydatin, resveratrol, anthraglycoside B, and emodin, showed inhibitory effects on glycolytic acid production and glucosyltransferase activity of S. mutans and S. sobrinus in addition to antibacterial activities.     

Pharmacokinetic study of luteolin,apigenin, chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract in rats

Flos Chrysanthemi (the flower of Chrysanthemum morifolium Ramat.) is widely used in China as a food and traditional Chinese medicine for many diseases. Luteolin and apigenin are two main bioactive components in Flos Chrysanthemi, and chrysoeriol and diosmetin are two methylated metabolites of luteolin in vivo by cathechol-O-methyltransferase (COMT). However, there was lack of pharmacokinetic information of chrysoeriol and diosmetin after oral administration of Flos Chrysanthemi extract (FCE). The present study aimed to develop an HPLC-UV method for simultaneous determination of rat plasma concentration of luteolin, apigenin, chrysoeriol and diosmetin and utilize it in pharmacokinetic study of the four compounds after orally giving FCE to rats. The method was successfully validated and applied to the pharmacokinetic study when oral administration of FCE to rats with or without co-giving a COMT inhibitor, entacapone. Chrysoeriol and diosmetin were detected in rat plasma after oral administration of FCE and their concentrations were significantly decreased after co-giving entacapone. Furthermore, AUC of luteolin was significantly increased by entacapone, while that of chrysoeriol was decreased by entacapone, which revealed COMT might play an important role in the disposition of luteolin in rats after dosing of FCE. In conclusion, a sensitive, accurate and reproducible HPLC-UV method for simultaneous determination of luteolin, apigenin, chrysoeriol and diosmetin in rat plasma were developed, pharmacokinetics of chrysoeriol and diosmetin combined with luteolin and apigenin were characterized after oral administration of FCE to rats, which gave us more information on pharmacokinetics and potential pharmacological effects of FCE in vivo.     

Role of herbal bioactives as a potential bioavailability enhancer for Active Pharmaceutical Ingredients

The current review emphasizes on the herbal bioenhancers which themselves do not possess inherent pharmacological activity of their own but when co-administered with Active Pharmaceutical Ingredients (API), enhances their bioavailability and efficacy. Herbal bioenhancers play a crucial role in enhancing the bioavailability and bioefficacy of different classes of drugs, such as antihypertensives, anticancer, antiviral, antitubercular and antifungal drugs at low doses. This paper highlights various natural compounds that can be utilized as an efficient bioenhancer. Several herbal compounds including piperine, quercetin, genistein, naringin, sinomenine, curcumin, and glycyrrhizin have demonstrated capability to improve the pharmacokinetic parameters of several potent API. This article also focuses on various United States patents on herbal bioenhancers, which has proved to be beneficial in improving oral absorption of nutraceuticals like vitamins, minerals, amino acids and certain herbal compounds. The present paper also describes proposed mechanism of action, which mainly includes absorption process, drug metabolism, and action on drug target. The herbal bioenhancers are easily available, safe, free from side effects, minimizes drug toxicity, shortens the duration of treatment, lowers the drug resistance problems and minimizes the cost of treatment. Inspite of the fact that herbal bioenhancers provide an innovative concept for enhancing the bioavailability of several potent drugs, there are numerous bioenhancers of herbal origin that are yet to be explored in several vital areas. These bioenhancers must also be implied to enhance the bioavailability and bioefficacy through routes other than the oral route of drug delivery. There is a vast array of unexploited plants which can be investigated for their drug bioenhancing potency. The toxicity profiles of these herbal bioenhancers must not be overlooked. Researches must be carried out to solve these issues and to deliver a safe and effective dose of drugs to attain desired pharmacological response.     

The studies of anti-inflammatory and analgesic activities and pharmacokinetics of Oxytropis falcate Bunge extraction after transdermal administration in rats

The aim of this study was to evaluate the activities of anti-inflammatory and analgesic of the total flavonoids extraction from Oxytropis falcate Bunge (FEO) after transdermal administration. The pharmacokinetics and absolute bioavailability of FEO in rat, furthermore, was studied. Firstly, the anti-inflammatory and analgesic effects of the FEO were studied by xylene-induced ear edema, adjuvant-induced joint inflammation law in rats, acetic acid-induced writhing and hot-plate tests in mice. Secondly, we developed a sensitive and specific HPLC method to analyze 2′, 4′-dihydroxychalcone (TFC, the mainly ingredient of FEO) in rat plasma to study the pharmacokinetic of TEC. The results showed FEO has anti-inflammatory and analgesic property in a dose-dependent manner, and that the high dose group (90.6 mg/kg) of FEO appeared more significantly effective than the positive drug. From the pharmacokinetic studies of TFC in rats, we got the main pharmacokinetic parameters of TFC, providing a basis for the future studies in clinic.     

HPLC-based activity profiling of Angelica pubescens roots for new positive GABAA receptor modulators in Xenopus oocytes

A petroleum ether extract of the traditional Chinese herbal drug Duhuo (roots of Angelica pubescens Maxim. f. biserrata Shan et Yuan), showed significant activity in a functional two-microelectrode voltage clamp assay with Xenopus oocytes which expressed recombinant γ-aminobutyric acid type A (GABA_A) receptors of the subtype α₁β₂γ_2S. HPLC-based activity profiling of the active extract revealed six compounds responsible for the GABA_A receptor modulating activity. They were identified by microprobe NMR and high resolution mass spectrometry as columbianetin acetate (1), imperatorin (3), cnidilin (4), osthol (5), and columbianedin (6). In concentration-dependent experiments, osthol and cnidilin showed the highest potentiation of the GABA induced chloride current (273.6% ± 39.4% and 204.5% ± 33.2%, respectively at 300 μM). Bisabolangelone (2) only showed minor activity at the GABA_A receptor. The example demonstrates that HPLC-based activity profiling is a simple and efficient method to rapidly identify GABA_A receptor modulators in a bioactive plant extract.     

Comparative pharmacokinetics of baicalin in normal and the type 2 diabetic rats after oral administration of the Radix scutellariae extract

Radix scutellariae was used alone or in combination with other medicinal herbs in the treatment of type 2 diabetes mellitus in China. At present, the pharmacokinetics of baicalin in type 2 diabetic rats following oral administration of Radix scutellariae extract was investigated. The results showed that the pharmacokinetics (especially AUC) of baicalin in type 2 diabetic rats after oral administration of Radix scutellariae extract was remarkably different from that in normal rats. Then the mechanism which resulted in the increased AUC of baicalin in diabetic rats was investigated from system clearance and presystemic metabolism. And it was found that the increased AUC of baicalin in diabetic rats at least partly resulted from higher production of baicalein in the intestinal tract of type 2 diabetic rats. Moreover, the activity of β-glucuronidase in intestinal mucosa of type 2 diabetic rats was demonstrated to be higher than that in normal rats, which confirmed the results above. In conclusion, the pharmacokinetic behavior of baicalin was significantly altered in type 2 diabetic rats after orally administrated Radix scutellariae extract, which may partly result from the increased activity of intestinal β-glucuronidase under the pathological state of type 2 diabetes mellitus.     

Antifeedent and toxic activity of endophytic Alternaria alternata against tobacco caterpillar Spodoptera litura

Fungal endophytes play a significant role in plant resistance to insects by altering the nutritional quality of plants or by production of various alkaloid-based defensive compounds. Ethyl acetate extract of endophytic Alternaria alternata isolated from Azadirachta indica A. Juss was tested for its bioactivity against Spodoptera litura (Fab.). Effect of different concentrations of ethyl acetate extract of A. alternata was assessed on growth and development of S. litura larvae. The results indicate higher larval mortality on diet supplemented with the fungal extract than control. Adverse effects of A. alternata were also observed on development of the insect. Ethyl acetate extract of the fungus also significantly reduced the adult emergence, longevity and reproductive potential of S. litura. Larvae feeding on diet supplemented with fungal extract showed significant reduction in relative growth and consumption rate, as well as efficiency of ingested and digested food. The antifeedant and toxic effects of A. alternata may be due to production of bioactive molecules by this fungus.     

Glomexanthones A–C,three xanthonolignoid C-glycosides from Polygala glomerata Lour

Three novel xanthonolignoid C-glycosides, glomexanthones A–C, with a trans-dihydrobenzofuran on B ring and a 2-hydroxymethyl-5-hydroxyl-2-pentenoic acid moiety in the sugar chain were isolated from an ethanol extract of Polygala glomerata. Their structures and absolute configurations were characterized by extensive NMR, MS, and CD spectroscopic studies. Screening results indicated that compounds 1–3 showed moderate neuroprotective effects on l-Glutamic acid-induced cellular damage in human neuroblastoma SK-N-SH cells.     

High performance liquid chromatographic analysis and anticancer potential of Oplopanax horridus: Comparison of stem and berry extracts

Oplopanax horridus or devil's club is a herbal medicine distributed in North America. The constituents and pharmacological activities of O. horridus (OPH) are largely unknown. In this study, we assayed OPH stem and berry extracts using high performance liquid chromatography (HPLC). The anticancer potentials of extracts on different human cancer cell lines (SW-480, HCT-116, HT-29, MCF-7 and NSCLC) were determined by MTS method. The effect of stem extract on cancer cell cycle, expression of cyclin A, and apoptosis were assayed using flow cytometry. HPLC data showed that the composition of OPH stem extract is more complicated than the berry extract. The wavelength of maximum absorption of the major constituent in stem and berry is 196.0 nm and 201.9 nm, respectively. Compared to the berry extract, the stem extract showed significant potent antiproliferative effect on all the studied cell lines. The stem extract at 0.1 mg/ml arrested cancer cells in S- and G2/M-phases, and significantly induced expression of cyclin A. After treatment with 0.1 mg/ml of stem extract for 72 h, apoptotic cells were increased to 45.2%, while control was 9.6%. The cell cycle arrest and induction of apoptosis may play a critical role in cancer chemoprevention by Oplopanax horridus stem extract.     

Diastereomers of lithospermic acid and lithospermic acid B from Monarda fistulosa and Lithospermum erythrorhizon

Monardic acids A (1) and B (2), which are (7R,8R) diastereomers of lithospermic acid (LA) and lithospermic acid B, respectively, were isolated from Monarda fistulosa. A (7S,8R) isomer (3) of LA was also isolated from this plant, and a (7R,8S) isomer (7) of LA was obtained from Lithospermum erythrorhizon. The absolute configuration of 1 was confirmed by analysis of its hydrolysates, 7-epiblechnic acid and 2R-3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid. The configuration in the dihydrobenzofuran moieties of 2, 3, and 7 was extrapolated by using the phenylglycine methyl ester method and a Cotton effect at approximately 250–260 nm in their electronic circular dichroism spectra. Diastereomers (1–3 and 7) displayed moderate hyaluronidase inhibitory and histamine release inhibitory activities.