Enhanced Cancer-targeted Drug Delivery Using Precoated Nanoparticles.

While protein coronas (PCs) are an important barrier in the clinical application of nanomedicines, the specific effects of PCs on nanoparticles (NPs) in vivo are unclear. Herein, we demonstrated that PCs from clinical sources greatly influenced the active targeting capacities of transferrin-modified NPs (Tf-NPs). Compared to PCs from healthy volunteers, PCs from the plasma of patients with nonsmall cell lung cancer (NSCLC) decreased the A549 uptake of Tf-NPs to a greater degree. The PC proteome revealed that this difference may be mediated by certain proteins in plasma. To attenuate the negative influence of PCs from patients, precoating Tf-NPs with PCs derived from healthy mice significantly enhanced active targeting capacities. Paclitaxel-loaded Tf-NPs with PCs derived from healthy mice showed the strongest antitumor effects in mice with NSCLC. This work illustrates the influence of PCs of ligand-modified NPs in clinical practice and proposes the use of corona-enabled active targeting for precision nanomedicine.

Physiologically Based Pharmacokinetic Modeling of Oxycodone in Children to Support Pediatric Dosing Optimization.

PURPOSE: Physiologically-based pharmacokinetic (PBPK) modeling offers a unique modality to predict age-specific pharmacokinetics. The objective of this study was to assess the ability of PBPK model to predict plasma exposure of oxycodone, a widely used opioid for pain management, in adults and children. METHODS: A full PBPK model of oxycodone following intravenous and oral administration was developed using a 'bottom-up' and 'top-down' combined strategy. The model was then extrapolated to pediatrics through a reasonable scaling method. The adult and pediatric model was evaluated using data from 17 clinical PK studies by testing predicted/observed goodness of fit. The mean fold error for PK parameters was calculated. Finally, we used the validated PBPK model to visualize adult-children dose conversion for oxycodone. RESULTS: The developed PBPK model successfully predicted the oxycodone disposition in adults, wherein the predicted versus observed AUC, Cmax, and tmax were within 0.90 to 1.20-fold difference. After scaling anatomy/physiology, protein binding, and clearance, the model showed satisfactory prediction performance for pediatric populations as predicted AUC were within the 1.50-fold range of the observed values. According to the application of PBPK model, we found that different intravenous doses should be given in children of different ages compared to a standard 0.1 mg/kg in adults, while a progressive increasing dose with age growth following oral administration is recommended for children. CONCLUSIONS: The current example provides the opportunity for using the PBPK model to guide dose adjustment of oxycodone in the design of future pediatric clinical studies.

Formulation conditions on the drug loading properties of polymeric micelles.

Methyl poly(ethylene glycol) grafted poly (lactide-co-(glycolic acid)-alt-(glutamic acid) amphiphilic copolymers (PLG-g-mPEG) were fabricated polymeric micelles to load anticancer drug doxorubicin (DOX). Both blank and drug loaded micelles were spherical nanoparticles with the mean sizes around 50 and 100nm, respectively. The effects of formulation conditions including compositions, concentrations, temperature, feeding doses and solvents on the size and drug loading content were investigated, the storage of the drug loaded micelles was explored. The results showed that the short graft mPEG chain length was favorable for the loading of DOX. The increase of temperature was preferable for receive micelles with higher drug loading content and smaller size. The encapsulation of polymeric micelles could protect the bioactivity of DOX. In vitro drug release profiles illustrated that the drug release from polymeric micelles with long mPEG chains was much faster than from micelles with short mPEG chains. The release kinetics of drug from micelles fitted to the Ritger-Peppas equation well and the release process followed diffusion mechanism.

[Advances in the research of pharmacogenomics of tamoxifen].

Tamoxifen (TAM) is the most common nonsteroidal antiestrogen agent, which has been widely used in the prevention of recurrence of estrogen or progesterone receptor-positive breast cancer in patients. It is metabolized by cytochrome P450 oxidases to its active metabolite (4-hydroxytamoxifen, 4-OH-TAM) and endoxifen (EDF), which played a critical role in the therapy. 4-OH-TAM and EDF have 30- to 100-fold more potency than TAM in the suppression of estrogen-dependent breast cancer cell proliferation. CYP3A4 and CYP2D6, as the key drug-metabolizing enzymes in those metabolic actions, are known to have several alleles. Genetic polymorphisms of CYP2D6 and CYP3A4 will influence the plasma concentrations of active TAM metabolites and clinical outcomes for breast cancer patients treated with TAM. The genetic polymorphisms of drug transporters, involved in the disposition of active TAM metabolites, also have the potential to influence the plasma concentrations of active TAM metabolites and clinical outcome for the treatment of breast cancer. In this review, we summarized the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the metabolism and disposition of TAM with the metabolite concentration, efficacy and adverse effects of TAM, which provides a fundamental reference for further pharmacogenomic study and clinical use of TAM.

[Transplacental transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia of MDCKII/MDCKII-BCRP cell line].

To study the transport mechanisms of drugs for transplacental treatment of fetal tachyarrhythmia, MDCKII-BCRP and MDCKII cell models was used. MDCKII-BCRP and MDCKII cell monolayer model was used to investigate the bi-direction transport of sotalol, propranolol, propafenone, procainamide and flecainide. Drug concentrations were measured by HPLC-UV or chemiluminescence. The apparent permeability coefficient (P(app)), efflux rate (R(E)) and net efflux rate (R(net)) were calculated. Drugs with R(net) greater than 1.5 were further investigated using cellular accumulation experiments with or without a BCRP inhibitor. The R(net) of sotalol, propranolol, propafenone and procainamide were less than 1.5, while R(net) of flecainide with concentrations of 20 and 5 µmol x L(-1) were 1.6 and 1.9, respectively. The results showed that the transport of flecainide on MDCKII-BCRP cell monolayer could be mediated by BCRP; and the affinity increased when the concentration of flecainide decreased. Cellular accumulation experiments further suggested that accumulation of flecainide in MDCKII-BCRP cells was significantly lower than that in MDCKII cells in a concentration-dependent manner. BCRP inhibitor quercetin (50 µmol x L(-1)) significantly increased the accumulation of flecainide in MDCKII-BCRP cells (P < 0.05). Our preliminary data showed that flecainide but not sotalol, propranolol, propafenone or procainamide can be a substrate of BCRP. Thus the effect of flecainide may be affected by the BCRP in the maternal placental trophoblast membrane layer when treating fetal tachyarrhythmia.

[Determination of Desloratadine and Its Metabolite 3-OH Desloratadine in Human Plasma by LC-MS/MS].

OBJECTIVE: To develop a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of desloratadine and its metabolite 3-OH desloratadine in human plasma. METHODS: 24 healthy male volunteers received a single oral dose of 5 mg desloratadine tablets in a randomized crossover bioequivalence study with two preparations of tablets. Serial plasma samples were taken and analyzed by the LC-MS/MS method. The pharmacokinetic parameters of the two preparations were calculated and compared statistically to evaluate their bioequivalence using Winnonlin 6. 3. RESULTS: The calibration curves of desloratadine and 3-OH desloratadine were both linear over the concentration range of 0. 050-6. 0 ng/mL, with intra-batch and inter-batch relative standard deviations less than 15%. The 90% confidence intervals (CIs) of peak concentration (Cmax) area under the curve (AUC)0t and AUC0-∞ of desloratadine and 3-OH desloratadine all resided within the bioequivalence limit 80%-125%. No significant difference in peak time (Tmax) was demonstrated between the two preparations. CONCLUSION: The LC-MS/MS method can be used for simultaneous determination of desloratadine and 3-OH desloratadine in human plasma, which has been successfully applied-to a bioequivalence study.

[Enhancers on the transmembrane transport of chlorogenic acid].

To investigate the influence of the difference enhancers on the transport mechanism of chlorogenic acid (CGA) across Caco-2 cells model, a RP-HPLC method was adopted to detect the concentrations of CGA. At the concentrations of 20 to 80 microg x mL(-1), the difference of absorption rate constants (K(a)) was not statistically significant. At the concentrations of 40 and 20 microg x mL(-1), the ratios of apparent permeability coefficients (P(app)) of the apical to basolateral and the basolateral to apical were 1.14 and 1.18, respectively. With the effect of enhancers K(a) and P(app) increased, the absorption half-life (T1/2) decreased. CGA passed through the Caco-2 cell membrane mainly by passive transport. It showed that monocarboxylic acid transporter (MCT) could be involved in the across membrane transport process of CGA. Borneol had no effect on the cell membrane transport processes. The order of increasing absorption of CGA caused by the enhancers was sodium lauryl sulphate > sodium taurocholate > carbomer.

PXR polymorphisms and their impact on pharmacokinetics/pharmacodynamics of repaglinide in healthy Chinese volunteers.

PURPOSE: CYP3A4 is the main isoform of cytochrome P450 oxidases involved in the metabolism of approximately 60 % drugs, and its expression level is highly variable in human subjects. CYP3A4 is regulated by many transcription factors, among which the pregnane X receptor/steroid and xenobiotic receptor (PXR/SXR, NR1I2) have been identified as the most critical. Genetic polymorphisms (such as SNPs) in PXR may affect the expression level of CYP3A4. Although numerous SNPs have been identified in PXR and have appeared to affect PXR function, their impact on the expression of CYP3A4 in human subjects has not been well studied. Thus, a clinical study in healthy Chinese subjects was conducted to investigate the impact of PXR polymorphisms on repaglinide (an endogenous marker for CYP3A4 activity) pharmacokinetics used alone or in combination with a PXR inducer, flucloxacillin. METHOD: Two SNPs, -298A>G and 11193T>C, were identified as the tag SNPs to represent the overall genetic polymorphic profile of PXR. To evaluate the potential functional change of these two SNPs, 24 healthy subjects were recruited in a pharmacokinetics/pharmacodynamics study of repaglinide with or without flucloxacillin. RESULTS: The pharmacokinetic parameters including AUC and T1/2 were significantly different among the PXR genotype groups. The SNPs of -298G/G and 11193C/C were found to be associated with a lower PXR activity resulting in reduction of CYP3A4 activity in vivo. After administration of flucloxacillin, a significant drug-drug interaction was observed. The clearance of repagnilide was significantly increased by concomitant flucloxacillin in a genotype dependent manner. The subjects with SNPs of -298G/G and 11193C/C appeared to be less sensitive to flucloxacillin. CONCLUSION: Our study results demonstrated for the first time the impact of genetic polymorphisms of PXR on the PK and PD of repaglinide, and showed that subjects with genotype of -298G/G and 11193C/C in PXR has a decreased elimination rate of 3A4/2C8. Furthermore, flucloxacillin was able to induce 3A4/2C8 expression mediated by PXR in a genotype dependent manner.

Assessment and modulation of phillyrin absorption by P-gp using Caco-2 cells and MDR1-MDCKII cells.

The study was to investigate the absorption mechanism and transport modulation of phillyrin by P-gp in Caco-2 cells and MDR1-MDCKII cells. Three concentrations of phillyrin were tested in transport studies. The absorptive transports of phillyrin in the two cell models were not concentration-dependent which indicated passive diffusion as the dominating process in the test concentrations. The absorptive P (app) were 7.15, 6.39 and 10.03 × 10(-6) cm s(-1), respectively, for different concentrations (2.2, 4.8 and 8.4 µg ml(-1)) in Caco-2 cells. And the low absorptive P (app) was consistent with the low oral bioavailability of phillyrin observed in pharmacokinetic experiments. In transport inhibition experiment, the efflux inhibitors, verapamil and GF120918 can increase the absorption of phillyrin in Caco-2 cells which suggested the involvement of efflux transporters. In the further inhibition experiment in MDR1-MDCKII cells, the absorption was greatly increased and the efflux of phillyrin was competitively inhibited by verapamil and GF120918, which confirmed the involvement of P-gp in the efflux of phillyrin.

Investigation on the absorption of phillyrin and forsythiaside in rat digestive tract.

In the present study, an in situ rat model was employed to systemically investigate the absorption of phillyrin and forsythiaisde. Three concentrations of phillyrin (0.2, 0.4 and 1.5 mg) were tested and the results showed that phillyrin cannot be absorbed in the digestive tract. The absorption rates of forsythiaside in stomach were 7.773, 7.228 and 6.751% h(-1) for 0.5, 1 and 2.5 mg, and no significant difference was found in different concentrations. The absorptions of forsythiaside in intestine were investigated in different concentrations and different absorption sites. The mean P% were 6.618, 7.199, 9.210 and 9.747% h(-1) of forsythiaside in intestine for 0.25, 0.5, 1, 2.5 mg dosage, and the statistical analysis showed that the absorption had no relation with concentration. In addition, in different digestive segments, the mean P% were 7.528, 8.382, 8.191, 9.109 and 6.908% h(-1) for the gastric, duodenum, jejunum, ileum and colon, respectively. No statistical differences of absorption were found for forsythiaside among different digestive segments indicated no specific absorption site was found.

Erratum.

Colon cancer (CC) is the third most common cancer worldwide. Emodin is an anthraquinone-active substance that has the ability to affect tumor progression. Our study aims to explore the effects and the relevant mechanism of emodin on the invasion and migration of CC in vitro and in vivo. In our study, we found that emodin inhibited the invasion and migration abilities of RKO cells and decreased the expression of matrix metalloproteinase-7 (MMP-7), MMP-9, and vascular endothelial growth factor (VEGF) in a dose-dependent manner. Further research suggested that emodin inhibited EMT by increasing the mRNA level of E-cadherin and decreasing the expression of N-cadherin, Snail, and -catenin. Emodin also significantly inhibited the activation of the Wnt/-catenin signaling pathway by downregulating the expression of related downstream target genes, including TCF4, cyclin D1, and c-Myc. A Wnt/-catenin signaling pathway agonist abolished the effect of emodin on EMT and cell mobility, suggesting that emodin exerted its regulating role through the Wnt/-catenin pathway. The CC xenograft model was established to study the antitumor efficiency of emodin in vivo. The in vivo study further demonstrated that emodin (40 mg/kg) suppressed tumor growth by inhibiting EMT via the Wnt/-catenin signaling pathway in vivo. Taken together, we suggest that emodin inhibits the invasion and migration of CC cells in vitro and in vivo by blocking EMT, which is related with the inhibition of the Wnt/-catenin signaling pathway.

Metabolite identification, tissue distribution, excretion and preclinical pharmacokinetic studies of ET-26-HCl, a new analogue of etomidate.

ET-26-HCl, a novel anaesthetic agent with promising pharmacological properties, lacks extensive studies on pharmacokinetics and disposition in vitro and in vivo. In this study, we investigated the metabolic stability, metabolite production and plasma protein binding (PPB) of ET-26-HCl along with its tissue distribution, excretion and pharmacokinetics in animals after intravenous administration. Ultra-high performance liquid chromatography-tandem quadrupole time-of-flight mass spectrometry identified a total of eight new metabolites after ET-26-HCl biotransformation in liver microsomes from different species. A hypothetical cytochrome P450-metabolic pathway including dehydrogenation, hydroxylation and demethylation was proposed. The PPB rate was highest in mouse and lowest in human. After intravenous administration, ET-26-HCl distributed rapidly to all tissues in rats and beagle dogs, with the highest concentrations in fat and liver. High concentrations of ET-26-acid, a major hydroxylation metabolite of ET-26-HCl, were found in liver, plasma and kidney. Almost complete clearance of ET-26-HCl from plasma occurred within 4 h after administration. Only a small fraction of the parent compound and its acid form were excreted via the urine and faeces. Taken together, the results added to a better understanding of the metabolic and pharmacokinetic properties of ET-26-HCl, which may contribute to the further development of this drug.

L-Ornithine-l-aspartate in the management of hepatic encephalopathy: a meta-analysis.

BACKGROUND AND AIM: Hepatic encephalopathy continues to be a major clinical problem and the current decade has not witnessed major therapeutic breakthroughs in this area. L-ornithine-l-aspartate (LOLA) is not frequently used as there are still some reservations about its benefits. The present study aimed to assess the effectiveness and safety of LOLA in the management of hepatic encephalopathy. METHODS: We used the method recommended by the Cochrane Collaboration to perform a meta-analysis of randomized controlled trials of LOLA therapy for hepatic encephalopathy including three randomized controlled trials. RESULTS: Three randomized trials randomizing 212 patients were included. LOLA versus placebo had a significant effect on improvement of hepatic encephalopathy (relative risk 1.89; 95% CI 1.32 to 2.71; P = 0.0005). This comparison showed no statistical heterogeneity (P = 0.85 and chi(2) = 0.09). Subgroup analysis showed that LOLA could be effective versus placebo in trials with grade I or II overt hepatic encephalopathy patients (relative risk 1.87; 95% CI 1.30 to 2.68; P = 0.0007) and had no significant effect in trials with subclinical hepatic encephalopathy patients (relative risk 1.69; 95% CI 0.72 to 3.94; P = 0.23). Adverse effects were observed in only three patients treated with LOLA in one report. CONCLUSIONS: LOLA benefited patients with overt hepatic encephalopathy (I or II), whereas these data do not support the use of LOLA for patients with subclinical hepatic encephalopathy.

Pharmacokinetics of phillyrin and forsythiaside following iv administration to Beagle dog.

The objective of the present study was to firstly investigate the in vivo pharmacokinetics of phillyrin and forsythiaside in beagle dog. On I.V. administration, a rapid distribution was observed and followed by a slower elimination for phillyrin and forsythiaside. The mean t(1/2Z) was 49.99, 34.87 and 43.81 min for 0.19, 0.70 and 1.43 mg/kg of phillyrin, and 60.90, 64.30, 57.99 min for 0.62, 1.39 and 5.52 mg/kg of forsythiaside respectively. And the AUC(o-t) increased linearly from 36.51 to 160.22 microg x min/ml of phillyrin and from 50.63 to 681.08 microg x min/ml after the three dosage administrated. In the range of the dose examined, the pharmacokinetics of phillyrin and forsythiaside in beagle dog was based on first order kinetics. Although both drugs were widely distributed to various tissues in the dog, no concerns about extensive binding to tissues that may be consumed by the public should a dog be exposed to phillyrin and forsythiaside according to the rapid elimination.

Emodin Inhibits Colon Cancer Cell Invasion and Migration by Suppressing Epithelial-Mesenchymal Transition via the Wnt/ß-Catenin Pathway.

Colon cancer (CC) is the third most common cancer worldwide. Emodin is an anthraquinone-active substance that has the ability to affect tumor progression. Our study aims to explore the effects and the relevant mechanism of emodin on the invasion and migration of CC in vitro and in vivo. In our study, we found that emodin inhibited the invasion and migration abilities of RKO cells and decreased the expression of matrix metalloproteinase-7 (MMP-7), MMP-9, and vascular endothelial growth factor (VEGF) in a dose-dependent manner. Further research suggested that emodin inhibited EMT by increasing the mRNA level of E-cadherin and decreasing the expression of N-cadherin, Snail, and ß-catenin. Emodin also significantly inhibited the activation of the Wnt/ß-catenin signaling pathway by downregulating the expression of related downstream target genes, including TCF4, cyclin D1, and c-Myc. A Wnt/ß-catenin signaling pathway agonist abolished the effect of emodin on EMT and cell mobility, suggesting that emodin exerted its regulating role through the Wnt/ß-catenin pathway. The CC xenograft model was established to study the antitumor efficiency of emodin in vivo. The in vivo study further demonstrated that emodin (40 mg/kg) suppressed tumor growth by inhibiting EMT via the Wnt/ß-catenin signaling pathway in vivo. Taken together, we suggest that emodin inhibits the invasion and migration of CC cells in vitro and in vivo by blocking EMT, which is related with the inhibition of the Wnt/ß-catenin signaling pathway.

MDR1 genotypes do not influence the absorption of a single oral dose of 600 mg valacyclovir in healthy Chinese Han ethnic males.

AIMS: To investigate the influence of three single nucleotide polymorphisms (SNPs) in exon 12 (C1236T), exon 21 (G2677T/A) and exon 26 (C3435T) of MDR1 gene on the absorption of valacyclovir after a single oral administration in the Chinese Han ethnic population. METHODS: Two hundred healthy Chinese subjects were genotyped for the SNPs of C1236T, G2677T/A and C3435T in the MDR1 gene using allele-specific polymerase chain reaction. Linkage disequilibrium (LD) was analysed. Twenty-four subjects derived from a large random sample (n = 200) received a single oral dose of 600 mg valacyclovir. Plasma concentrations of acyclovir were determined up to 14 h after administration to obtain a pharmacokinetic profile. RESULTS: LD existed between G2677T/A in exon 21 and C3435T in exon 26 (P < 0.001), between C1236T in exon 12 and C3435T (P < 0.001), but not between C1236T and G2677T/A (P > 0.05). C(max), AUC(0-1.5 h) and AUC(0-infinity) were used as indices of valacyclovir absorption. AUC(0-infinity) for the 2677TA genotype was 17.45 +/- 2.40 microg x h/ml, which was much higher compared with the 2677GG, GA and TT genotypes of 10.44 +/- 1.00, 11.84 +/- 2.83, 11.34 +/- 2.32 microg x h/ml, respectively (P < 0.05). Similarly, a statistically significant difference of AUC(0-infinity) was also observed for different linked genotypes at position 2677 vs. 3435, and 1236 vs. 3435 (P < 0.05). However, there was no significant difference in valacyclovir absorptive pharmacokinetics between carriers and noncarriers of different haplotypes (P > 0.05). CONCLUSIONS: Three SNPs of MDR1 gene did not influence the absorption of a single oral dose of 600 mg valacyclovir in healthy Chinese Han ethnic subjects.

Intra-herb pharmacokinetics interaction between quercetin and isorhamentin.

AIM: Quercetin and isorhamnetin are common constituents of some herb extracts, such as extracts of gingko leaves and total flavones of Hippophae rhamnoides L. The intra-herb pharmacokinetics interactions between isorhamnetin and quercetin were investigated in the present study. METHODS: Human MDR1 cDNA transfected MDCKII cells were used to validate whether isorhamnein interacted with P-gp. Caco-2 transport assays and a randomized, 3-way crossover pharmacokinetics study in rats were used to investigate the pharmacokinetics interactions. HPLC was used to determine cell transport samples. The total plasma concentrations of quercetinand isorhamnetin were determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) by treatment with beta-glucuronidase and sulfatase. RESULTS: The permeability ratio (absorptive permeability/secretive permeability) of isorhamnetin across human MDR1 cDNA transfected MDCKII cells, Caco-2 cells and wild-type MDCKII cells are 0.25+/-0.02, 0.74+/-0.05, and 1.41+/-0.06, respectively. This result proved the role of P-gp in the cell efflux of isorhamnetin. While co-transporting with each other across Caco-2 cells monolayer, the permeability ratio of isorhamnetin and quercetin increased by 4.3 and 2.2 times. After coadministration with each other to rats, the C(max), AUC(0-72 h), and AUC(0-infinity) of both isorhamnetin and quercetin significantly increased compared with single administration. CONCLUSION: The above results proved intra-herb pharmacokinetics interaction between quercetin and isorhamentin. P-gp might play an important role, whereas other drug efflux pumps, such as multi-drug resistance associate protein 2 and breast cancer resistance protein, might be involved. Accordingly, besides the drug-herb interactions, intra-herb interaction might be brought into view with the wide use of herbal-based remedies.

[Investigation on pharmacokinetics of helicid in rats].

OBJECTIVE: To report the pharmacokinetic parameters of helicid HD in rats after intravenous administration at different doses. METHOD: Fifteen Wistar rats were randomly assigned as three groups (n=5, male) to be given helicid solution via tail vein injection at a single dose of 2.23, 4.46, 6.70 mg x kg(-1), respectively. Blood samples were collected via tail vein at time intervals after HD injection. 6% perchloric acid was to precipitate plasma protein. Separation was achieved on a reversed-phase C18 column with UV detection at 270 nm. RESULT: The calibration curves were linear ranging from 43.8 to 43,800 microg x L(-1). The intra-and inter-day precisions were no more than 6%. The average recovery of helicid was more than 87% from plasma. With minimum akaike information criterion (AIC) values, a two-compartment open pharmacokinetic model was proposed and validated through the DAS 2.0 to explain the apparent diphasic phenomenon of (HD) in rat blood after intravenous administration. Helicid appeared to be distributed rapidly into a highly perfused central compartment (first compartment), with a less rapidly elimination. The diphasic phenomenon could be observed from the compartment model parameters t(1/2alpha) and t(1/2beta). The least squares regression analysis indicated that the plasma concentrations and AUC of helicid in rat plasma were proportional to the administrated doses. At the administrated doses of 2.23, 4.46, 6.70 mg x kg(-1), the values of distribution half-life (t(1/2alpha)) were 4.582, 5.097, 4.727 min, respectively. And the values of elimination half-life (t(1/2beta)) were 23.945, 26.508 and 25.396 min, respectively. The volume of distribution from these three different doses were 0.036, 0.035, 0.035 L, respectively. The AUCo(0-->t) (area under the concentration-time curve) increase was proportional to the administrated dose. CONCLUSION: In the range of the doses examined, the pharmacokinetics of helicid in rats is based on linear dynamics.

Enhancement of oral bioavailability and immune response of Ginsenoside Rh2 by co-administration with piperine.

Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides in Panax ginseng. However, the oral bioavailability of Rh2 is low, with P-glycoprotein (P-gp) and CYP3A4 being reported to be the main factors. The purpose of the present study was to determine the enhancing effect of piperine on the oral bioavailability as well as bioactivity of Rh2. The inhibitory effect of piperine on P-gp and CYP3A4 was determined using a Caco-2 monolayer model and a recombinant CYP3A4 metabolic system, respectively. The pharmacokinetics of oral Rh2 (10 mg·kg-1) administered alone or in combination with piperine (10 and 20 mg·kg-1) was performed in rats. The immune boosting effect of Rh2 was assessed in rats by measuring IL-12 level after treated by Rh2 alone or co-administered with piperine. The results indicated that piperine significantly increased the permeability of Rh2 and inhibited the metabolism of Rh2. The pharmacokinetic study results showed that the AUC of Rh2 was significantly increased in combination with piperine at high dose (20 mg·kg-1) when compared to the control group, with relative bioavailability of 196.8%. The increase of Rh2 exposure led to increased serum levels of IL-12. In conclusion, piperine may be used as a bioenhancer to improve pharmacological effect of Rh2 when given orally.

Simultaneous determination of vitexin-4''-O-glucoside and vitexin-2''-O-rhamnoside from Hawthorn leaves flavonoids in rat plasma by HPLC method and its application to pharmacokinetic studies.

The present study was to investigate the pharmacokinetics of the two similar flavonoid glycosides, vitexin-4''-O-glucoside (VGL) and vitexin-2''-O-rhamnoside (VRH) in rats after intravenous administration of hawthorn leaves flavonoids (HLF). Blood samples were collected via tail vein at time intervals after drug administration and the plasma concentrations of the studied ingredients were analyzed by HPLC after the plasma protein was precipitated directly with methanol. VGL and VRH were successfully separated using a C(18) column with a UV detection at 330 nm and a mobile phase of methanol-acetonitrile-tetrahydrofuran-0.5% acetic acid (1:1:19.4:78.6, v/v/v/v). The assay linearities of VGL and VRH were confirmed over the range 0.23-138.42 and 0.36-218.49 microg/ml, respectively. The accuracy and precision of the two analytes at high, medium and low concentration were within the range of -3.13% to 3.51% and below 4%, the mean assay recoveries of them (n=5) ranged from 96.87% to 101.75% and 96.88% to 103.51% for intra- and inter-day assays and the mean extraction recoveries of them (n=5) varied from 92.68% to 95.74% for VGL and 93.45% to 99.26% for VRH, respectively. After intravenous administration of HLF to rats over the doses range of 10-40 mg/kg, the plasma concentration--time curves of VGL and VRH were both conformed to the three-compartment open pharmacokinetic model and linear pharmacokinetic characteristics.