Preparation, Characterization, Wound Healing, and Cytotoxicity Assay of PEGylated Nanophytosomes Loaded with 6-Gingerol.

BACKGROUND: Nutrients are widely used for treating illnesses in traditional medicine. Ginger has long been used in folk medicine to treat motion sickness and other minor health disorders. Chronic non-healing wounds might elicit an inflammation response and cancerous mutation. Few clinical studies have investigated 6-gingerol's wound-healing activity due to its poor pharmacokinetic properties. However, nanotechnology can deliver 6-gingerol while possibly enhancing these properties. Our study aimed to develop a nanophytosome system loaded with 6-gingerol molecules to investigate the delivery system's influence on wound healing and anti-cancer activities. METHODS: We adopted the thin-film hydration method to synthesize nanophytosomes. We used lipids in a ratio of 70:25:5 for DOPC(dioleoyl-sn-glycero-3-phosphocholine): cholesterol: DSPE/PEG2000, respectively. We loaded the 6-gingerol molecules in a concentration of 1.67 mg/mL and achieved size reduction via the extrusion technique. We determined cytotoxicity using lung, breast, and pancreatic cancer cell lines. We performed gene expression of inflammation markers and cytokines according to international protocols. RESULTS: The synthesized nanophytosome particle sizes were 150.16 ± 1.65, the total charge was -13.36 ± 1.266, and the polydispersity index was 0.060 ± 0.050. Transmission electron microscopy determined the synthesized particles' spherical shape and uniform size. The encapsulation efficiency was 34.54% ± 0.035. Our biological tests showed that 6-gingerol nanophytosomes displayed selective antiproliferative activity, considerable downregulation of inflammatory markers and cytokines, and an enhanced wound-healing process. CONCLUSIONS: Our results confirm the anti-cancer activity of PEGylated nanophytosome 6-gingerol, with superior activity exhibited in accelerating wound healing.

Role of Sulphur and Heavier Chalcogens on the Antioxidant Power and Bioactivity of Natural Phenolic Compounds.

The activity of natural phenols is primarily associated to their antioxidant potential, but is ultimately expressed in a variety of biological effects. Molecular scaffold manipulation of this large variety of compounds is a currently pursued approach to boost or modulate their properties. Insertion of S/Se/Te containing substituents on phenols may increase/decrease their H-donor/acceptor ability by electronic and stereo-electronic effects related to the site of substitution and geometrical constrains. Oxygen to sulphur/selenium isosteric replacement in resveratrol or ferulic acid leads to an increase in the radical scavenging activity with respect to the parent phenol. Several chalcogen-substituted phenols inspired by Vitamin E and flavonoids have been prepared, which in some cases prove to be chain-breaking antioxidants, far better than the natural counterparts. Conjugation of catechols with biological thiols (cysteine, glutathione, dihydrolipoic acid) is easily achieved by addition to the corresponding ortho-quinones. Noticeable examples of compounds with potentiated antioxidant activities are the human metabolite 5-S-cysteinyldopa, with high iron-induced lipid peroxidation inhibitory activity, due to strong iron (III) binding, 5-S-glutathionylpiceatannol a most effective inhibitor of nitrosation processes, and 5-S-lipoylhydroxytyrosol, and its polysulfides that proved valuable oxidative-stress protective agents in various cellular models. Different methodologies have been used for evaluation of the antioxidant power of these compounds against the parent compounds. These include kinetics of inhibition of lipid peroxidation alkylperoxyl radicals, common chemical assays of radical scavenging, inhibition of the OH• mediated hydroxylation/oxidation of model systems, ferric- or copper-reducing power, scavenging of nitrosating species. In addition, computational methods allowed researchers to determine the Bond Dissociation Enthalpy values of the OH groups of chalcogen modified phenolics and predict the best performing derivative. Finally, the activity of Se and Te containing compounds as mimic of glutathione peroxidase has been evaluated, together with other biological activities including anticancer action and (neuro)protective effects in various cellular models. These and other achievements are discussed and rationalized to guide future development in the field.

Antineutrophil properties of natural gingerols in models of lupus.

Ginger is known to have antiinflammatory and antioxidative effects and has traditionally been used as an herbal supplement in the treatment of various chronic diseases. Here, we report antineutrophil properties of 6-gingerol, the most abundant bioactive compound of ginger root, in models of lupus and antiphospholipid syndrome (APS). Specifically, we demonstrate that 6-gingerol attenuates neutrophil extracellular trap (NET) release in response to lupus- and APS-relevant stimuli through a mechanism that is at least partially dependent on inhibition of phosphodiesterases. At the same time, administration of 6-gingerol to mice reduces NET release in various models of lupus and APS, while also improving other disease-relevant endpoints, such as autoantibody formation and large-vein thrombosis. In summary, this study is the first to our knowledge to demonstrate a protective role for ginger-derived compounds in the context of lupus. Importantly, it provides a potential mechanism for these effects via phosphodiesterase inhibition and attenuation of neutrophil hyperactivity.

Novel pH-Sensitive Urushiol-Loaded Polymeric Micelles for Enhanced Anticancer Activity.

PURPOSE: The aim of this study was to develop a means of improving the bioavailability and anticancer activity of urushiol by developing an urushiol-loaded novel tumor-targeted micelle delivery system based on amphiphilic block copolymer poly(ethylene glycol)-b-poly-(ß-amino ester) (mPEG-PBAE). MATERIALS AND METHODS: We synthesized four different mPEG-PBAE copolymers using mPEG-NH2 with different molecular weights or hydrophobicity levels. Of these, we selected the mPEG5000-PBAE-C12 polymer and used it to develop an optimized means of preparing urushiol-loaded micelles. Response surface methodology was used to optimize this formulation process. The micellar properties, including particle size, pH sensitivity, drug release dynamics, and critical micelle concentrations, were characterized. We further used the MCF-7 human breast cancer cell line to explore the cytotoxicity of these micelles in vitro and assessed their pharmacokinetics, tissue distribution, and antitumor activity in vivo. RESULTS: The resulting micelles had a mean particle size of 160.1 nm, a DL value of 23.45%, and an EE value of 80.68%. These micelles were found to release their contents in a pH-sensitive manner in vitro, with drug release being significantly accelerated at pH 5.0 (98.74% in 72 h) without any associated burst release. We found that urushiol-loaded micelles were significantly better at inducing MCF-7 cell cytotoxicity compared with free urushiol, with an IC50 of 1.21 mg/L. When these micelles were administered to tumor model animals in vivo, pharmacokinetic analysis revealed that the total AUC and MRT of these micelles were 2.28- and 2.53-fold higher than that of free urushiol, respectively. Tissue distribution analyses further revealed these micelles to mediate significantly enhanced tumor urushiol accumulation. CONCLUSION: The pH-responsive urushiol-loaded micelles described in this study may be ideally suited for clinical use for the treatment of breast cancer.

A Mixture of Phenolic Metabolites of Quercetin Can Decrease Elevated Blood Pressure of Spontaneously Hypertensive Rats Even in Low Doses.

Quercetin is proven to decrease arterial blood pressure when given orally. Its bioavailability is, however, low and, therefore, its metabolites could rather be responsible for this effect. In particular, the colonic metabolites of quercetin, 3,4-dihydroxyphenylacetic acid (DHPA), 4-methylcatechol (4MC), and 3-(3-hydroxyphenyl)propionic acid (3HPPA), have been previously shown to decrease the blood pressure in spontaneously hypertensive rats (SHR). Interestingly, the mechanisms of action of these three metabolites are different. The aim of this study is hence to investigate if these metabolites can potentiate each other and thus decrease blood pressure in reduced doses. Three double-combinations of previously mentioned metabolites were administered to SHR as infusions to mimic a real biological situation. All combinations significantly decreased the blood pressure in SHR but there were important differences. The effect of DHPA and 4MC was mild and very short. A combination of DHPA with 3HPPA caused more pronounced effects, which were also rather short-lived. The last combination of 3HPPA and 4MC caused a long-lasting effect. In conclusion, certain combinations of quercetin metabolites have a more pronounced antihypertensive effect than single metabolites.

Preparation and in vitro/in vivo evaluation of 6-Gingerol TPGS/PEG-PCL polymeric micelles.

6-Gingerol, an active herbal ingredient of ginger has various bioactivities such as anti-neurodegenerative disease, anti-inflammatory and so on. The aim of the present study was to enhance the oral bioavailability and brain distribution of 6-Gingerol via polymeric micelles. A polymeric micelles drug delivery system of 6-Gingerol consisting of D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) and Poly (ethylene glycol)-poly (ε-caprolactone) (PEG-PCL) was prepared via solvent injection method. The developed 6-Gingerol-loaded TPGS/PEG-PCL micelles (6-GTPMs) were characterized based on particle size, polydispersity index (PDI), zeta potential, encapsulation efficiency (EE), drug loading (DL) and in vitro release profile. The pharmacokinetics and tissue distribution studies were also evaluated. The nanoformulation produced a particle size of 73.24 ± 2.84 nm with acceptable PDI (0.129 ± 0.03), zeta potential (-2.74 ± 0.92 mV), DL (4.64%) and EE (79.68%). The in vitro release profile showed that the 6-GTPMs enhanced the solubility of 6-Gingerol, while the pharmaceutical analysis in rats indicated that 6-GTPMs significantly improved the oral bioavailability of 6-Gingerol (about 3 folds) in circulation. The 6-GTPMs exhibited remarkable brain targetability in the tissue distribution analysis. Collectively, a 6-Gingerol polymeric micelle with enhanced oral bioavailability coupled with excellent brain distribution was successfully developed.

Blood-brain barrier permeability study of ginger constituents.

Ginger, the rhizome of Zingiber officinale Roscoe is of great importance in the traditional medicine for the treatment of various diseases. More than 400 constituents have been reported in the plant, the most important ones being the gingerol and shogaol derivatives. Positive effects of ginger extracts and isolated [6]-gingerol have been proved in animal models of anxiety, Alzheimer's disease, Parkinson's disease and epilepsy. Taken in consideration these promising positive effects of ginger and its constituents in the central nervous system, the isolation of gingerol and shogaol derivatives ([6]-gingerol (1), [8]-gingerol (2), [10]-gingerol (3), [6]-shogaol (4), [10]-shogaol (5), 1-dehydro-[6]-gingerdione (6), 1-dehydro-[10]-gingerdione (7)) and investigation of their transcellular passive diffusion across the blood-brain barrier (BBB) were carried out. For this purpose, a Parallel Artificial Membrane Permeability Assay for the Blood-Brain Barrier (PAMPA-BBB) was chosen that had previously been validated for natural compounds. Based on our results, [6]-gingerol, [8]-gingerol and [6]-shogaol were found to be able to penetrate the BBB via passive diffusion, suggesting them to contribute to the positive effects of ginger extracts in the central nervous system.

[6]-Shogaol/ß-CDs inclusion complex: preparation, characterisation, in vivo pharmacokinetics, and in situ intestinal perfusion study.

Aims: The aim was to improve the absorption and bioavailability of [6]-shogaol with ß-cyclodextrin (ß-CD) prior to in vitro and in vivo evaluation. Methods: [6]-Shogaol/ß-CDs inclusion complexes (6-S-ß-CDs) were developed using saturated aqueous solution method and characterised with appropriate techniques. The absorption and bioavailability potential of [6]-shogaol was evaluated via in vivo pharmacokinetics and in situ intestinal perfusion. Results: The results of characterisation showed that 6-S-ß-CDs (drug loading, 7.15%) were successfully formulated. In vitro release study indicated significantly improved [6]-shogaol release. Pharmacokinetic parameters such as Cmax, AUC0-36 h, and oral relative bioavailability (about 685.36%) were substantially enhanced. The in situ intestinal perfusion study revealed that [6]-shogaol was markedly absorbed via passive diffusion in the intestinal segments, and duodenum followed by ileum and jejunum. Conclusions: Cyclodextrin inclusion technology could enhance the intestinal absorption and oral bioavailability of hydrophobic drugs like [6]-shogaol.

Development of sustained-release pellets to modulate the in vivo processes of the main active components of Danshen: A pharmacokinetic and pharmacodynamic evaluation.

BACKGROUND: Danshen is a first-line traditional Chinese medicine derived from Salvia miltiorrhiza Bunge consisting mainly of tanshinone IIA, tanshinol, protocatechuic aldehyde, and salvianolic acid B, it is widely used to treat cardiovascular diseases based on the synergistic effect of its multiple active components. Recent studies have indicated that the overall effect of traditional Chinese medicine is closely related to the in vivo coexistence of a variety of active components. HYPOTHESIS: The prolongation of the coexistence of the four active components in Danshen in vivo by regulating their pharmacokinetic processes may contribute to better efficiency. METHODS/STUDY DESIGNS: Individual sustained-release pellets of the four main active components in Danshen were respectively prepared according to the optimised formulations developed in our previous studies to modulate their in vivo processes, in which the desired release profiles of each kind of sustained-release pellets for formulation optimisation were calculated based on the point-area deconvolution and circadian rhythm of variant angina. The four kinds of sustained-release pellets were filled into capsules on the basis of the original weight ratio of the four active components in purified Salvia miltiorrhiza extract for further in vitro release and pharmacokinetic and pharmacodynamic investigations. RESULTS: The release behaviours of the combined Danshen capsules composed of the four kinds of sustained-release pellets were evaluated in three media with different pH levels (pH 1.2, 6.8, and pure water). The release profiles of each kind of sustained-release pellets in pH 6.8 PBS and pH 1.2 HCl were similar to the release profile of those in pure water (similarity factors f2 > 50). Pharmacokinetic studies revealed that the four kinds of sustained-release pellets in the combined Danshen capsules possessed the same Tmax and similar and extended MRT. Moreover, pharmacodynamic studies indicated that the combined Danshen capsules had much better anti-angina effects than commercial Danshen capsules according to comprehensive evaluations via electrocardiogram, serum index (CK-MB, cTn-I, ET, and NO), myocardial oxidative damage, and myocardial pathologic biopsy. CONCLUSION: Sustained-release preparations can markedly prolong the in vivo coexistence of multiple components in Danshen to enhance their overall effects, which provides a potent strategy for developing the combination therapy of traditional Chinese medicine.

Pharmacokinetics and Tissue Distribution of Gingerols and Shogaols from Ginger (Zingiber officinale Rosc.) in Rats by UPLC⁻Q-Exactive⁻HRMS.

Gingerols and shogaols are recognized as active ingredients in ginger and exhibit diverse pharmacological activities. The preclinical pharmacokinetics and tissue distribution investigations of gingerols and shogaols in rats remain less explored, especially for the simultaneous analysis of multi-components. In this study, a rapid, sensitive, selective, and reliable method using an Ultra-Performance Liquid Chromatography Q-Exactive High-Resolution Mass Spectrometer (UPLC-Q-Exactive⁻HRMS) was established and validated for simultaneous determination of eight compounds, including 6-gingerol, 6-shogaol, 8-gingerol, 8-shogaol, 10-gingerol, 10-shogaol, Zingerone, and 6-isodehydrogingenone in plasma and tissues of rats. The analytes were separated on a Syncronis C18 column (100 × 2.1 mm, 1.7 µm) using a gradient elution of acetonitrile and 0.1% formic acid in water at a flow rate of 0.25 mL/min at 30 °C. The method was linear for each ingredient over the investigated range with all correlation coefficients greater than 0.9910. The lowest Lower Limit of quantitation (LLOQ) was 1.0 ng/mL. The intra- and inter-day precisions (Relative Standard Deviation, RSD%) were less than 12.2% and the accuracy (relative error, RE%) ranged from -8.7% to 8.7%. Extraction recovery was 91.4⁻107.4% and the matrix effect was 86.3⁻113.4%. The validated method was successfully applied to investigate the pharmacokinetics and tissue distribution of eight components after oral administration of ginger extract to rats. These results provide useful information about the pharmacokinetics and biodistribution of the multi-component bioactive ingredients of ginger in rats and will contribute to clinical practice and the evaluation of the safety of a Chinese herbal medicine.

A novel electrochemical nanosensor based on NH2-functionalized multi walled carbon nanotubes for the determination of catechol-orto-methyltransferase inhibitor entacapone.

In this study, an antiparkinson drug Entacapone (ENP) is electrochemically investigated under optimized conditions using NH2 functionalized multi walled carbon nanotubes (NH2fMWCNT) decorated over glassy carbon electrode (GCE). The surface morphology of the NH2fMWCNT/GCE was probed by scanning electron microscopy (SEM) armed with EDX analysis. Electrochemical impedance spectroscopy (EIS) was employed to investigate the electron transfer capability of modified and bare electrodes. Cyclic voltammetry was used to compare the redox response of ENP on the surface of modified and unmodified electrodes. The influence of interfering agents was also studied to examine the selectivity of the designed sensor. For the purpose of practical applicability of the proposed method, differential pulse voltammetric method was applied for the investigation of ENP in real samples i.e., tablet, human serum and urine. Almost 100% recovery percentages were obtained from tablet, serum and urine samples with RSD% values of less than 2% for all the samples, thus, suggesting promising applicability of the designed electrochemical sensing platform (NH2fMWCNT/GCE) for determination of ENP in pharmaceutical dosage and real samples.

Formulation, Characterization, and Pharmacokinetic Studies of 6-Gingerol-Loaded Nanostructured Lipid Carriers.

In this study, an optimized nanostructured lipid carriers (NLCs) were developed and investigated for improving the solubility and oral availability of 6-Gingerol (6G), an active and abundant component of ginger with limited applications due to its poor water solubility plus oral biological availability. The NLCs consisted of a solid lipid (glyceryl monostearate), another liquid lipid (decanoyl/octanoyl-glycerides) and mixed surfactants (Tween 80 and Poloxamer 188), and was prepared by high pressure homogenization method. The optimal 6G-NLC formulation was evaluated through physical properties such as appearance, mean particle size, zeta potential, encapsulation efficiency, and in vitro drug release, alongside techniques viz., transmission electron microscopy (TEM), differential scanning calorimetry (DSC), as well as powder X-ray diffraction (XRD). Pharmacokinetics were also evaluated in rats. The 6G-NLCs prepared with optimal formulation exhibited a homogenous spherical shape with mean particle size and zeta potential of 63.59 ± 5.54 nm and - 12.18 ± 1.06 mV. Encapsulation efficiency and drug loading were 76.71 ± 1.11 and 1.17 ± 0.35%, respectively. In vitro release profile of 6G from NLCs was sustained and fitted with Weibull equation. After oral administration of the 6G-NLCs, drug concentrations in serum, MRT, and AUC0-t were significantly higher as compared with the free 6G suspension. All these results indicated that the developed NLC formulation could be effective and promising drug carriers to improve the water solubility of 6G while sustaining the drug release as well as prolonging in vivo acting time of the drug coupled with oral bioavailability enhancement.

Enhanced oral bioavailability and anti-gout activity of [6]-shogaol-loaded solid lipid nanoparticles.

[6]-Shogaol, an alkylphenol compound purified from the root and stem of ginger (Zingiber officinale), has attracted considerable interest due to its potential anticancer, antioxidative and antirheumatic properties. However, the oral bioavailability of [6]-shogaol has been severely limited because of its poor solubility. In this study, a significant quantity of high-purity [6]-shogaol (yield: 3.6%; purity: 98.65%) was extracted and encapsulated in solid lipid nanoparticles (SLNs) via high-pressure homogenization (encapsulation efficiency: 87.67%) to improve its solubility and oral bioavailability. The resulting [6]-shogaol-loaded solid lipid nanoparticles (SSLNs) were stable, homogeneous and well-dispersed. Its mean particle size and zeta potential were 73.56 ±â€¯5.62 nm and -15.2 ±â€¯1.3 mV, respectively. Importantly, the in vitro release profile and in vivo oral bioavailability of SSLNs were significantly improved compared with the free drug. Furthermore, the SSLNs could remarkably lower the uric acid level via inhibiting the activity of xanthine oxidase and reduce the production of interleukin-1ß (IL-1ß) and tumor necrosis factor (TNF-α) in the hyperuricemia/gouty arthritis rat model, when compared to the free [6]-shogaol. Collectively, SLNs could serve as a promising drug delivery system to improve the oral bioavailability of [6]-shogaol for effective treatment of gouty arthritis.

Phytosome complexed with chitosan for gingerol delivery in the treatment of respiratory infection: In vitro and in vivo evaluation.

Respiratory infection is a viral spreading disease and a common issue, particularly in kids. The treatments are available but have so many limitations because the drawback of this disease is more morbidity and mortality in the severely immune compromised. Even, the phyto-constituent antibacterial drug Gingerol was selected to treat respiratory infection but it exhibits low bioavailability profile, less aqueous-solubility issue and most important is rapidly eliminated from the body. To overcome these problems, novel drug delivery (nanoparticle) based phytosome complexed with chitosan approach was implemented. In this research work, the phytosome (GP) was prepared by blending of gingerol with soya lecithin in organic solvent using anti-solvent precipitation technique and it was further loaded in the aqueous solution of chitosan to formulate the phytosome complexed with chitosan (GLPC). To optimize the formulations of gingerol, it was characterized for percentage yield, percentage entrapment efficiency, drug loading and particle size, physical compatibility studies etc. which demonstrated the confirmation of complex of GLPC with soya lecithin and chitosan. The % entrapment efficiency and % drug loading of GLPC was found (86.02 ±â€¯0.18%, 08.26 ±â€¯0.72%) and of GP (84.36 ±â€¯0.42%, 08.05 ±â€¯0.03%), respectively. The average particle size and zeta potential of GLPC and GP were 254.01 ±â€¯0.05 nm (-13.11 mV), and 431.21 ±â€¯0.90 nm (-17.53 mV), respectively which confirm the inhibition of particle aggregation by using chitosan in complex. The in vitro release rate of GP (86.03 ±â€¯0.06%) was slower than GLPC (88.93 ±â€¯0.33%) in pH 7.4 phosphate buffer up to 24 h by diffusion process (Korsmeyer Peppas model). The optimized GLPC and GP were shown irregular particle shapes & spherical and oval structures with smooth surface by SEM analysis. Furthermore, GLPC has shown the potent in vitro antioxidant activity, susceptible antibacterial activity and effective anti-inflammatory activity as compared to GP against stress, microbial infection and inflammation which were causable reason for the respiratory infections. GLPC has improved the significant bioavailability and also correlated the hematological values on rabbit blood against the incubation of microorganisms. Thus, the prepared nanoparticle based approach to deliver the gingerol, has the combined effect of chitosan and phytosome which shown better sustained-release profile and also prolonging the oral absorption rate of gingerol with effective antibacterial activity to treat respiratory infection.

Pharmacokinetic Study on Protocatechuic Aldehyde and Hydroxysafflor Yellow A of Danhong Injection in Rats with Hyperlipidemia.

BACKGROUND: Protocatechuic aldehyde (PAL) and hydroxysafflor yellow A (HSYA) are 2 effective ingredients of Danhong Injection, which is extensively used for the clinical treatment of cardio-cerebrovascular diseases. This study aims to investigate the pharmacokinetic differences between single and combined medication of PAL and HSYA and analyze the interaction of the above effective components in hyperlipidemia rats. METHODS: Thirty male SD rats were randomly divided into the control group (n = 6) and the model group (n = 24). The hyperlipidemia model was established by feeding with superfatted forage. The successful model rats were then randomly divided into the PAL group (16 mg/kg), the HSYA group (10 mg/kg), and the combination group (16 mg/kg + 10 mg/kg). Administration through tail-vein, and orbital blood was sampled at different time points. The mass concentration of PAL and HSYA was determined by high performance liquid chromatography (HPLC-DAD). Analysis of pharmacokinetic parameters was conducted by using DAS 3.2.6 software and SPSS 19.0 statistical analysis software. RESULTS: According to the parameters of statistical moment of non-compartmental model, there was a significant difference in plasma clearance (CL) between the PAL group and the drug combination group (p < 0.01), as well as in the area under the first moment of the plasma concentration-time curve and the elimination half-life (t1/2) between the HSYA group and the drug combination group (p < 0.01) but no obvious differences about the blood concentration time curve area, the average dwell time (MRT), and the peak concentration (Cmax; p > 0.05). CONCLUSION: The combined medication of PAL and HSYA could increase the plasma CL significantly and have a great influence on the absorption of HSYA in rats with hyperlipidemia.

Improved Bioavailability of Levodopa Using Floatable Spray-Coated Microcapsules for the Management of Parkinson's Disease.

Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation.

Pharmacokinetic-pharmacodynamic correlations in the development of ginger extract as an anticancer agent.

Anticancer efficacy of ginger phenolics (GPs) has been demonstrated in various in vitro assays and xenograft mouse models. However, only sub-therapeutic plasma concentrations of GPs were detected in human and mouse pharmacokinetic (PK) studies. Intriguingly, a significant portion of GPs occurred as phase II metabolites (mainly glucuronide conjugates) in plasma. To evaluate the disposition of GPs and understand the real players responsible for efficacy, we performed a PK and tissue distribution study in mice. Plasma exposure of GPs was similar on day 1 and 7, suggesting no induction or inhibition of clearance pathways. Both free and conjugated GPs accumulated in all tissues including tumors. While non-cytotoxicity of 6-ginerol glucuronide precluded the role of conjugated GPs in cell death, the free forms were cytotoxic against prostate cancer cells. The efficacy of ginger was best explained by the reconversion of conjugated GPs to free forms by ß-glucuronidase, which is over-expressed in the tumor tissue. This previously unrecognized two-step process suggests an instantaneous conversion of ingested free GPs into conjugated forms, followed by their subsequent absorption into systemic circulation and reconversion into free forms. This proposed model uncovers the mechanistic underpinnings of ginger's anticancer activity despite sub-therapeutic levels of free GPs in the plasma.

Effects of Phytochemical P-Glycoprotein Modulators on the Pharmacokinetics and Tissue Distribution of Doxorubicin in Mice.

Pungent spice constituents such as piperine, capsaicin and [6]-gingerol consumed via daily diet or traditional Chinese medicine, have been reported to possess various pharmacological activities. These dietary phytochemicals have also been reported to inhibit P-glycoprotein (P-gp) in vitro and act as an alternative to synthetic P-gp modulators. However, the in vivo effects on P-gp inhibition are currently unknown. This study aimed to test the hypothesis that phytochemical P-gp inhibitors, i.e., piperine, capsaicin and [6]-gingerol, modulate the in vivo tissue distribution of doxorubicin, a representative P-gp substrate. Mice were divided into four groups and each group was pretreated with intraperitoneal injections of control vehicle, piperine, capsaicin, or [6]-gingerol and doxorubicin (1 mg/kg) was administered via the penile vein. The concentrations of the phytochemicals and doxorubicin in the plasma and tissues were determined by LC-MS/MS. The overall plasma concentration-time profiles of doxorubicin were not significantly affected by piperine, capsaicin, or [6]-gingerol. In contrast, doxorubicin accumulation was observed in tissues pretreated with piperine or capsaicin. The tissue to plasma partition coefficients, Kp, for the liver and kidney were higher in the piperine-pretreated group, while the Kp for kidney, brain and liver were higher in the capsaicin-pretreated group. [6]-Gingerol did not affect doxorubicin tissue distribution. The data demonstrated that the phytochemicals modulated doxorubicin tissue distribution, which suggested their potential to induce food-drug interactions and act as a strategy for the delivery of P-gp substrate drugs to target tissues and tumors.

Pharmacokinetic interaction of aconitine, liquiritin and 6-gingerol in a traditional Chinese herbal formula, Sini Decoction.

1. This study aimed to investigate the pharmacokinetic interaction of the three ingredients in a traditional Chinese herbal formulation, Sini Decoction, and provide evidence for its compatibility mechanism. 2. First, the effect of liquiritin and 6-gingerol on the pharmacokinetic parameters of aconitine was investigated in rats by using a sensitive and reliable LC-MS/MS method. Then the Caco-2 cell monolayer model and Rhodamine-123 uptake assay were used to investigate the effect of liquiritin and 6-gingerol on the absorption of aconitine and the activity of P-gp. 3. The Cmax of aconitine increased significantly (p < 0.05) from 10.34 ± 1.99 to 17.68 ± 2.65 ng/mL with the pretreatment of liquiritin (20 mg/kg), and to 17.43 ± 0.96 ng/mL with 6-gingerol (20 mg/kg). When aconitine was co-administered with liquiritin and 6-gingerol, the Cmax and AUC(0-t) of aconitine increased approximately twofold, and while t1/2 only increased 1.2-fold. The Caco-2 cell monolayer model and Rhodamine-123 uptake assay indicated that both liquiritin and 6-gingerol could increase the absorption of aconitine by inhibiting the activity of P-gp. 4. These results indicated that both liquiritin and 6-gingerol could promote the absorption of aconitine and increase its drug concentration in blood by inhibiting the activity of P-gp, and it could also provide evidence for compatibility mechanism of the traditional Chinese herbal formula, Sini Decoction.