Solid dispersion and effervescent techniques used to prepare docetaxel liposomes for lung-targeted delivery system: in vitro and in vivo evaluation

A lung-targeting liposomal docetaxel was developed to improve therapeutic index and to reduce side effects. Docetaxel proliposomes composed of docetaxel/Tween-80/Phospholipon 90H/cholesterol/citric acid at molar ratio of 0.18:0.09:3.78:3.78:91.17 were prepared by solid dispersion technique, and then were hydrated with NaHCO₃ solution to obtain docetaxel liposomes by effervescent technique. The stability of proliposomes containing docetaxel, characterization and evaluation of lung-targeting effect of docetaxel liposomes in rabbit were studied. Docetaxel proliposomes were stable at 6?±?2°C for at least 12 months. The particle size, zeta-potential, and entrapment efficiency of the resulted liposomes were 1011?±?22?nm, ?23.7?±?0.26?mv, and 90.12?±?0.36%, respectively. As far as the targeting parameters are concerned, the relative intake rate (R_e) and the ratio of peak concentration (C_e) of lung were 28.91 and 74.28, respectively. Compared with liver, spleen, and kidney, the ratios of targeting efficacy (T_e)_liposomes to (T_e)_injection of lung were increased by a factor of 3.16, 23.00, and 27.83, respectively. In conclusion, the negatively charged docetaxel liposomes with diameter of about 1 µm described in this study have favorable lung-targeting effect and are a promising lung-targeting carrier.     

Oral administration of liposomes containing cyclosporine: a pharmacokinetic study

Liposomal formulation containing cyclosporine A (CSA) were prepared. The most stable liposomes with the composition of CSA, dipalmitoylphosphatidyl choline (DPPC) and cholesterol (Chol.) in molar ratio 1:0.2:1, respectively were administered orally to New Zealand rabbits. The pharmacokinetic of the administered CSA was compared with that of the commercially available oily oral formulation of CSA (Sandimmune) at dose of 15 mg/kg. Cyclosporine concentration in blood was monitored using a radioimmunoassay method (RIA). A change in the pharmacokinetic parameters of CSA due to liposomal encapsulation was observed. A peak concentration was reached in 50 min in case of liposomes compared with 225 min in case of Sandimmune. The rate of absorption (C_max/AUC_0–∞) was significantly faster following the liposome administration. A significant difference in the area under the concentration curve (AUC_0–∞) was found and this was attributed to the difference in the terminal half-lives (t_1/2β) which were 8.88±1.94 and 19.3±8.48 h for liposomes and Sandimmune preparations, respectively. The mean residence time (MRT) and the mean absorption time (MAT) were dramatically decreased following the administration of liposomal formulation. Generally, there was less inter-individual variation in the values of rate of absorption, t_1/2β and MRT when CSA liposomes were orally administered compared to the administration of Sandimmune. Thus, an oral liposomal formulation for CSA can be developed to offer the advantages of low variability and fast onset of action.     

AAPE proliposomes for topical atopic dermatitis treatment

Abstract

Context: Anti-inflammatory effect of advanced adipose stem cell derived protein extract (AAPE) could be improved by minimising protein degradation. Objective: To develop a proliposomal formulation of AAPE for the treatment of topical atopic dermatitis. Materials and methods: Proliposomal powder was manufactured by evaporating a solution of soy phosphatidyl choline, AAPE and Poloxamer 407 in ethanol under vacuum on sorbitol powder. Characterisation of proliposomes (zeta potential, diameter, stability and flowability) as well as in vivo efficacy in a dermatitis mouse model was investigated. Results and discussion: Reconstitution of the proliposomal powder formed liposomes of 589?±?3.6?nm diameter with zeta potential of ?51.33?±?0.36?mV. Protein stability was maintained up to 90 days at 25?°C as proliposomes. In vivo studies on atopic dermatitis mouse model showed a significant reduction in IgE levels after topical AAPE proliposome treatment. Conclusion: AAPE proliposomes maintained protein stability and showed promising results for atopic dermatitis treatment.     

Electrosteric stealth Rivastigmine loaded liposomes for brain targeting: preparation,characterization, ex vivo,bio-distribution and in vivo pharmacokinetic studies

Being one of the highly effective drugs in treatment of Alzheimer’s disease, Rivastigmine brain targeting is highly demandable, therefore liposomal dispersion of Rivastigmine was prepared containing 2?mol% PEG-DSPE added to Lecithin, Didecyldimethyl ammonium bromide (DDAB), Tween 80 in 1:0.02:0.25 molar ratio. A major challenge during the preparation of liposomes is maintaining a stable formulation, therefore the aim of our study was to increase liposomal stability by addition of DDAB to give an electrostatic stability and PEG-DSPE to increase stability by steric hindrance, yielding what we called an electrosteric stealth (ESS) liposomes. A medium nano-sized liposome (478?±?4.94?nm) with a nearly neutral zeta potential (ZP, ?8?±?0.2?mV) and an entrapment efficiency percentage of 48?±?6.22 was prepared. Stability studies showed no major alteration after three months storage period concerning particle size, polydispersity index, ZP, entrapment efficiency and in vitro release study confirming the successful formation of a stable liposomes. No histopathological alteration was recorded for ESS liposomes of the sheep nasal mucosa. While ESS liposomes showed higher % of drug permeating through the sheep nasal mucosa (48.6%) than the drug solution (28.7%). On completing the in vivo pharmacokinetic studies of 36 rabbits showed 424.2% relative bioavailability of the mean plasma levels of the formula ESS compared to that of RHT intranasal solution and 486% relative bioavailability of the mean brain levels.     

Elastic Liposomal Formulation for Sustained Delivery of Colchicine: In Vitro Characterization and In Vivo Evaluation of Anti-gout Activity

Colchicine, an alkaloid found in extracts of the plants Colchicum autumnale and Gloriosa superb, is effective in the treatment of acute gout and dermatological conditions like leuko-cytoclastic vasculitis, psoriasis, and Sweet’s syndrome. Oral administration of colchicine is associated with gastrointestinal side effects and its accumulation in the body leads to bone marrow suppression. In the present study, an attempt has been made for development and in vitro and in vivo evaluation of elastic liposomal formulation for topical delivery of colchicine. The in vitro skin permeation study across rat skin found transdermal flux for different elastic liposomal formulations to range between 32.8?±?1.2 and 44.4?±?1.9 μg h^?1 cm^?2, which was approximately seven to 11 times higher than obtained using drug solution (4.3?±?0.6 μg h^?1 cm^?2). The results of skin deposition study showed that elastic liposomal formulation provide 12.5-fold higher skin deposition as compared to drug solution of colchicine. Confocal laser scanning microscopy also revealed better accumulation and deeper penetration (up to 200 μm) of elastic liposomes than drug solution (up to 12 μm). The biological evaluation of various vesicular formulations and drug solution was carried out using monosodium urate-induced air pouch model. The results of anti-gout activity in rats showed better and sustained biological effects in 24 h measured in terms of exudate volume (63.1?±?5.7% and 9.6?±?0.5% reduction with elastic liposomes and drug solution, respectively), reduction in leukocyte count (74.2?±?6.0% and 4.1?±?0.3% reduction with elastic liposomes and drug solution, respectively), decrease in inflammatory cells accumulation, and collagen deposition with elastic liposomal formulation than drug solution. Hence, the present study reveals that elastic liposomal formulation of colchicine possesses greater potential to enhance skin accumulation, prolong drug release, and improve the site-specificity of colchicine.     

Formulation of plumbagin loaded long circulating pegylated liposomes: in vivo evaluation in C57BL/6J mice bearing B16F1 melanoma

Context and Objective: Plumbagin (2-methyl, 5-hydroxy, 1, 4-naphthoquinone), an anticancer agent is encapsulated either as conventional or long circulating liposomal formulations to enhance its biological half-life and antitumor efficacy.

Methods: The liposomes were prepared by thin film hydration method and in vitro characterization was carried out to examine the particle size, zeta potential, drug encapsulation efficiency and in vitro release. The optimized formulations were tested for pharmacokinetic and pharmacodynamic efficacy against mice bearing B16F1 melanoma. Also in vivo toxicity studies were carried out.

Results and Discussion: The optimum particle size and entrapment efficiency was observed at drug to lipid molar ratio of 1:20. The in-vitro release of plumbagin from the liposomal formulations in phosphate-buffered saline (pH 7.4) showed biphasic release with an initial burst release followed by sustained release phase. Elimination half life (T_1/2) of pegylated, conventional and free plumbagin was 1305.76?±?278.16, 346.87?±?33.82 and 35.89?±?7.95?min respectively. Further, plumbagin exhibited better antitumor efficacy in vivo when administered as long circulating liposomes with no signs of normal tissue toxicity.

Conclusion: It can be concluded that the pegylated liposomes could provide a promising parenteral platform for plumbagin with enhanced plasma half-life and therapeutic efficacy.     

Targeted delivery of levofloxacin-liposomes for the treatment of pulmonary inflammation

The present study systematically studied the intravenous injectable formulation of liposomes loaded with levofloxacin, an amphipathic antibiotic. The aim of the present study was to design passive targeting liposomes, which might improve the antibacterial activity by accumulating in lung and reduce side effects such as neurotoxicity and hematotoxicity associated with direct injection of the drug. Levofloxacin-loaded liposomes were prepared by the ammonium sulfate gradients method. The formulated liposomes were found to be relatively uniform in size (7.424 ± 0.689 μm) with a positive zeta potential (+13.11 ± 1.08 mV). The entrapment efficiency of levofloxacin-loaded liposomes ranged from 82.19% to 86.23%. The administered liposomes were composed of soybean phosphatides, cholesterol, levofloxacin, and sulfate which existed in inner liposomes. In vitro drug release was monitored for up to 3 days, and the release behavior was in accordance with the Weibull equation. The levofloxacin-loaded liposomes exhibited a longer elimination half-life (t_1/2β) in vivo compared with the levofloxacin solution after intravenous injection to New Zealand rabbits. The encapsulation of levofloxacin in liposomes also changed its biodistribution in mice after intravenous injection in caudal vein. Liposomal levofloxacin performed significant lung targeting efficiency with area under the concentration–time curve, targeting efficacy (Te), and The intake rate (Re) of lung, all showing obvious increase. In addition, liposomal formulations presented accumulative activity in spleen and liver. Conversely, the biodistribution of liposomal formulation in non-RES sites, such as kidney, brain, heart, and plasma, decreased with descending peak concentration ration (Ce) compared to levofloxacin injection, which potentially resulted in the reduction of the side effects of free drug. These results indicated that the levofloxacin-loaded liposomes were promising passive targeting to lung for pulmonary infection treatment.     

Preparation and optimisation of anionic liposomes for delivery of small peptides and cDNA to human corneal epithelial cells

Drug delivery to corneal epithelial cells is challenging due to the intrinsic mechanisms that protect the eye. Here, we report a novel liposomal formulation to encapsulate and deliver a short sequence peptide into human corneal epithelial cells (hTCEpi). Using a mixture of Phosphatidylcholine/Caproylamine/Dioleoylphosphatidylethanolamine (PC/CAP/DOPE), we encapsulated a fluorescent peptide, resulting in anionic liposomes with an average size of 138.8?±?34?nm and a charge of ?18.2?±?1.3?mV. After 2?h incubation with the peptide-encapsulated liposomes, 66% of corneal epithelial (hTCEpi) cells internalised the FITC-labelled peptide, demonstrating the ability of this formulation to effectively deliver peptide to hTCEpi cells. Additionally, lipoplexes (liposomes complexed with plasmid DNA) were also able to transfect hTCEpi cells, albeit at a modest level (8% of the cells). Here, we describe this novel anionic liposomal formulation intended to enhance the delivery of small cargo molecules in situ.     

Pharmacokinetics and bioequivalence of two strontium ranelate formulations after single oral administration in healthy Chinese subjects

1. Pharmacokinetics of exogenous strontium (Sr) and bioequivalence of a new oral formulation of strontium ranelate compared with the brand-name drug in healthy Chinese subjects was evaluated.

2. A balanced, randomized, single-dose, two-treatment parallel study was conducted in 36 healthy Chinese subjects. Subjects were randomly allocated into two groups of 18 to receive a single oral dose of test formulation and reference formulation under a fasting state, respectively. Blood samples were collected at 19 designated time points up to 240-h post-dose. Serum concentrations of Sr were quantified by ICP-MS.

3. A total of 36 subjects were enrolled and completed the study. Nine mild adverse events in 6 subjects were reported. The C_max, AUC_0–72?h, AUC_0–t, and AUC_0–∞ of test and reference formulations shown as mean?±?SD were 6.97?±?1.78 and 6.78?±?1.80?µg/mL, 199?±?51 and 187?±?38?µg·h/mL, 303?±?89 and 278?±?54?µg·h/mL, and 337?±?109 and 305?±?60?µg·h/mL, respectively.

4. Two formulations were bioequivalent, and both were generally well tolerated.

     

The pharmacokinetics of methotrexate after intravenous administration of methotrexate-loaded proliposomes to rats

The pharmacokinetics and tissue distribution of methotrexate (MTX) were investigated after intravenous (i.v.) injection of free MTX (treatment I), MTX-loaded proliposomes (treatment II), and empty proliposomes mixed manually with free MTX (treatment III), 8 mg kg^?1, to rats using an HPLC assay. After i.v. infusion in 1 min, the plasma concentration of MTX (C_p), the area under the plasma concentration-time curve (AUC, 639 versus 913 μg min mL^?1), the terminal half-life (t_1/2, 48.8 versus 397 min), the mean residence time (MRT, 8.40 versus 325 min), and the apparent volume of distribution at steady state (V_ss, 98.1 versus 2800 mL kg^?1) were significantly higher; however, the total body clearance (CL, 12.5 versus 8.76 mL min^?1 kg^?1), renal clearance (CL_R, 4.49 versus 2.78 mL min^?1 kg^?1), non-renal clearance (CL_NR, 7.50 versus 5.99 mL min^?1kg^?1), and the amount of MTX excreted in urine (X_u, 808 versus 685 μg, p < 0.0948) were significantly lower from treatment II than from treatment I. This could be due to the fact that some of the MTX-loaded liposomes (formed immediately after hydration of MTX-loaded proliposomes) are entrapped in tissues and the rest are present in the plasma (higher MRT and V_ss from treatment II), and MTX is slowly released from MTX-loaded liposomes (higher t_1/2 from treatment II). In the present HPLC assay, the concentrations of MTX represent the sum of free MTX and MTX loaded in liposomes (higher C_p and AUC, slower CL from treatment II). After i.v. infusion in 1 min, some pharmacokinetic parameters, such as t_1/2, MRT, and V_ss, were significantly different between treatments I and III; however, the differences seemed to be smaller than those between treatments I and II. After 30 min from i.v. infusion, the tissue to plasma (T/P) ratios of MTX in kidney and stomach from treatment II were significantly lower than those from treatment I. This suggested that the i.v. administration of MTX-loaded proliposomes might have fewer side effects in the organs than that of free MTX. The mean amount of MTX loaded in MTX-loaded proliposomes was 2.54 mg/g proliposomes and the MTX was released slowly from hydrated MTX-loaded proliposomes when incubated with phosphate-buffered saline (PBS), rat plasma, or rat liver homogenate.     

Preparation of itraconazole-loaded liposomes coated by carboxymethyl chitosan and its pharmacokinetics and tissue distribution

Liposomes are potential carriers for targeting and controlled drug delivery by the intravenous route. Carboxymethyl chitosan (CMC) is a ramification of chitosan with intrinsic water-solubility. The aim of this study is to prepare itraconazole-loaded liposomes coated by carboxymethyl chitosan (CMC-ITZ-Lips), to evaluate its physico-chemical characteristics and the tissue targeting after being injected intravenously (i.v.). This study uses a film dispersion method to prepare itraconazole-loaded liposomes (ITZ-Lips) prior to coating them with CMC. The concentrations of ITZ in selected organs were determined using reversed-phase high-performance liquid chromatography (HPLC) following i.v. administration of ITZ-Sol, ITZ-Lips, and CMC-ITZ-Lips. CMC-ITZ-Lips had an average diameter of 349.3?±?18?nm with a zeta potential of ?35.71?±?0.62 mV and the in vitro antifungal activity was not inhibited by the entrapment. The CMC-ITZ-Lips exhibited a longer elimination half life (t_1/2β) in vivo compared with ITZ-Sol and ITZ-Lips after i.v. injection to mice. The biodistribution in mice was also changed after ITZ was encapsulated in CMC coated liposomes. CMC-ITZ-Lips performed significant lung targeting efficiency with AUC, Te and Re of lung all showed obvious elevation. In this study itraconazole was successfully encapsulated into carboxymethyl chitosan-modified liposomes for application of injection.     

超滤法-HPLC法测定灯盏花素脂质体包封率

目的对灯盏花素脂质体进行质量评价,测定灯盏花素脂质体包封率。方法采用超滤法分离脂质体与游离药物;采用Kromasil ODS柱(200 mm×4.6 mm,5μm),流动相为甲醇乙腈20 mmol.L-1磷酸盐缓冲液(pH值为2.5)(体积比为17∶17∶66),流速为0.8 mL.min-1,检测波长为334 nm,测定药物含量,计算包封率。结果超滤法能很好的将脂质体与游离药物分离,游离药物的平均回收率在95.9%~97.6%,加样回收率在96.4%~97.1%,脂质体不能透过超滤膜;该色谱条件下,灯盏乙素得到良好分离,辅料不干扰测定,灯盏乙素在1.0~40.0 mg.L-1内线性关系良好(r=0.999 9),日内和日间RSD均小于2.0%(n=5),加样回收率在99.7%~100.1%之间,RSD小于1.23%。结论该方法可用于灯盏花素脂质体的质量控制。     

Toxicokinetic of flumethrin in rabbits

In this study, the toxicokinetic of flumethrin after single oral and intravenous applications were studied. For this aim, 14 male New Zealand rabbits were used. The animals were divided into two groups of seven each. While 10?mg/kg.bw of flumethrin was intravenously injected into the first group, the same dose was administered orally with the second group. Serial blood samples were also collected at certain periods. Flumethrin concentrations were measured using a gas chromatography with a micro electron capture detector. The serum flumethrin concentration-time curve was determined to fit a two-compartment open model. Among the parameters calculated following intravenous application of flumethrin, the half-life at β phase (t_1/2β), mean residence time (MRT) and area under the concentration time curve in 0–∞ (AUC_0→∞) values were respectively found to be 34.0?±?4.2?h, 48.0?±?5.8?h and 36.1?±?5.3. On the other hand, the maximal concentration in serum (C_max), time needed to reach C_max (t_max), t_1/2β, MRT and AUC_0→∞ values of flumethrin after oral administration were determined to be 0.54?±?0.09?μg/ml, 5.42?±?0.97?h, 43.3?±?8.6?h, 59.7?±?10.5?h and 22.0?±?2.0?mg.h/L, respectively. The bioavailability of flumethrin was found to be 60.9%. In conclusion, these results were considered to be important in terms of the toxication risk of flumethrin and its safe use.     

Intravenous delivery of a liposomal formulation of voriconazole improves drug pharmacokinetics,tissue distribution,and enhances antifungal activity

Voriconazole (VCZ), a triazole with a large spectrum of action is one of the most recommended antifungal agents as the first line therapy against several clinically important systemic fungal infections, including those by Candida albicans. This antifungal has moderate water solubility and exhibits a nonlinear pharmacokinetic (PK) profile. By entrapping VCZ into liposomes, it is possible to circumvent certain downsides of the currently available product such as a reduction in the rate of its metabolization into an inactive form, avoidance of the toxicity of the sulfobutyl ether-beta-cyclodextrin (SBECD), vehicle used to increase its solubility. PKs and biodistribution of VCZ modified by encapsulation into liposomes resulted in improved antifungal activity, due to increased specificity and tissue penetration. In this work, liposomal VCZ resulted in AUC_0–24/MIC ratio of 53.51?±?11.12, whereas VFEND^® resulted in a 2.5-fold lower AUC_0–24/MIC ratio (21.51?±?2.88), indicating favorable antimicrobial systemic activity. VCZ accumulation in the liver and kidneys was significantly higher when the liposomal form was used. Protection of the drug from biological degradation and reduced rate of metabolism leads to a 30% reduction of AUC of the inactive metabolite voriconazole-N-oxide (VNO) when the liposomal drug was administered. Liposomal VCZ presents an alternative therapeutic platform, leading to a safe and effective treatment against systemic fungal infections.     

Effects of Danshen tablets on pharmacokinetics of atorvastatin calcium in rats and its potential mechanism

Context: Danshen tablets (DST), an effective traditional Chinese multi-herbal formula, are often combined with atorvastatin calcium (AC) for treating coronary heart disease in the clinic.

Objective: This study investigated the effects of DST on the pharmacokinetics of AC and the potential mechanism.

Materials and methods: The pharmacokinetics of AC (1?mg/kg) with or without pretreatment of DST (100?mg/kg) were investigated using LC-MS/MS. The effects of DST (50?μg/mL) on the metabolic stability of AC were also investigated using rat liver microsome incubation systems.

Results: The results indicated that C_max (23.87?±?4.27 vs. 38.94?±?5.32?ng/mL), AUC_(0–t) (41.01?±?11.32 vs. 77.28?±?12.92?ng h/mL), and t_1/2 (1.91?±?0.18 vs. 2.74?±?0.23?h) decreased significantly (p?t_1/2) of AC was also decreased (25.7?±?5.2 vs. 42.5?±?6.1) with the pretreatment of DST.

Discussion and conclusions: This study indicated that the main components in DST could accelerate the metabolism of AC in rat liver microsomes and change the pharmacokinetic behaviors of AC. So these results showed that the herb-drug interaction between DST and AC might occur when they were co-administered. Therefore, the clinical dose of AC should be adjusted when DST and AC are co-administered.     

PHARMACOKINETIC EVALUATION OF LIPOSOMAL ENCAPSULATED AMPICILLIN IN MALE AND FEMALE RATS

The dispositions of free and liposomal entrapped ampicillin were compared in male and female rats after IV administration. Serial blood samples were collected for 2 h in the free drug study and 12 h for the liposomal formulation. Pharmacokinetic parameters obtained with free drug were not significantly different between genders. However, gender significantly influenced the disposition of liposomal encapsulated ampicillin. While no difference was observed in distribution t_1/2 between genders, female rats had a shorter MRT, smaller V_ss and V_t and faster clearance as compared to male rats. In a second study, spleen, liver, kidney, heart, and lung were harvested post-injection of free and liposomal entrapped ampicillin. Free ampicillin did not distribute extensively into the tissue compartment and no gender difference was noted. In contrast, liposomal encapsulation resulted in a substantial tissue uptake. In general, female rats had higher concentrations in the spleen and lung as compared to male rats. In vitro plasma stability was not significantly different, suggesting that destabilization of the liposomes does not play a large role in the dispositional differences observed in these studies. However, in vivo interaction of liposomes and plasma lipoproteins may influence the disposition of encapsulated drug. ©1997 by John Wiley & Sons, Ltd.     

Ocular ciprofloxacin hydrochloride mucoadhesive chitosan-coated liposomes

The aim of this work is to improve the ocular bioavailability of ciprofloxacin hydrochloride (CPX) through the preparation of ocular mucoadhesive chitosan (CS)-coated liposomes. Liposomes were prepared by the thin film hydration technique, using different molar ratios of L-α-phosphatidylcholine (PC), cholesterol (CH), stearylamine (SA) and dicetyl phosphate (DP). CS was used to coat the optimal liposomal formulae. The prepared formulae were characterized regarding encapsulation efficiency (%EE), particle size, physical morphology and in vitro drug release. The in vivo characterization of the prepared formulae was performed through evaluating the level of CPX in the external eye tissue of nine albino rabbits. Results showed an alteration in release rate and %EE of CPX from liposomal formulae upon varying the molar ratios of the lipid bilayer composition. The optimal liposomal formulae F1 (10:0, PC:CH), F12 (10:0:0.5, PC:CH:SA) and F15 (10:0:1, PC:CH:DP), showed % EE of 38.5?±?2.10, 39.65?±?1.85 and 30.05?±?0.75 and % in vitro release after 8 hours (Q_8h) of 78.15?±?2.4, 54.07?±?2.3 and 62.14?±?2.9, respectively. In vitro drug release and in vivo results confirmed that CS-coated liposomal formulae have exhibited a higher retention of CPX. Consequently, CS-coated liposomes could be a promising approach to increase the ocular bioavailability of CPX.     

Comparative pharmacokinetics of chlorogenic acid in beagles after oral administrations of single compound,the extracts of Lonicera japanica,and the mixture of chlorogenic acid,baicalin, and Forsythia suspense

Context: Chlorogenic acid (ChA) is the major compound in Shuang-Huang-Lian (SHL), which is mainly composed of ChA, baicalin, and Forsythia suspense Thunb Vahl.

Objective: The effects of co-existing compounds in SHL and Lonicera japanica Thunb on the absorption of ChA was investigated.

Materials and methods: According to 3?×?3 Latin-square test, ChA alone, the extracts of Lonicera japanica, or the mixture of ChA, baicalin and Forsythia suspense (ChA effective doses is 60?mg/kg) was separately given to six beagles for seven days. The oral pharmacokinetic parameters of ChA in plasma, urine and faeces were quantified by HPLC/UV and analyzed.

Results: The pharmacokinetic parameters of ChA alone, the extracts of Lonicera japanica, and the mixture of ChA, baicalin, and Forsythia suspense were as followed: C_max (2.350?±?0.483, 1.655?±?0.576, 2.332?±?0.606?μg/mL), AUC_0-∞ (6.324?±?1.853, 4.216?±?1.886, 6.074?±?1.473?μg·h/mL), t_1/2 (0.911?±?0.187, 1.204?±?0.309, 1.094?±?0.193?h), and T_max (1.861?±?0.499, 1.000?±?0.459, 1.833?±?0.279?h). Accumulative fraction excretion of ChA in urine were 0.73?±?0.55, 1.25?±?1.23, 1.05?±?0.96%, while that in faeces were 0.68?±?0.94, 0.19?±?0.40, and 1.76?±?3.57%.

Discussion and conclusion: Co-existing compounds in SHL have no effect on the absorption of ChA, while the concomitant compounds in Lonicera japanica could decrease that of ChA. ChA in Beagles might have high biological transformation.     

Metabolite profile analysis and pharmacokinetic study of emodin,baicalin and geniposide in rats

1. Emodin, baicalin and geniposide are the major bioactive components in Da-Huang, Huang-Qin and Zhi-Zi which are herbal medicines widely used in Asian nations.

2. The metabolism of the three compounds was found to undergo hydroxylation, decarboxylation, dehydration, methylation, hydrolysis, hydrogenation, dihydrogenation, sulfation, glucosidation and/or glucuronidation. A total of 63 metabolites were detected in urine, plasma and bile of rats given a mixture of the three compounds.

3. Pharmacokinetic properties of the three compounds were determined in rats given the extracts of Da-Huang, Huang-Qin and Zhi-Zi. The pharmacokinetic parameters for emodin, baicalin and geniposide were found to be 0.13?±?0.11, 0.25?±?0.12 and 0.40?±?0.09?h (T_max); 21?±?9, 1515?±?254 and 482?±?50?ng/mL (C_max); 8.6?±?5.5, 18.3?±?2.8 and 22.1?±?17.2?h (t_1/2); 29?±?20, 16886?±?3734 and 2936?±?551?ng/mL?h (AUC_(0–t)); and 37?±?20, 22624?±?6295 and 3582?±?820?ng/mL?h (AUC_(0–∞)).

4. The metabolism and pharmacokinetic studies facilitate appropriate employment of Da-Huang, Huang-Qin and Zhi-Zi in clinic.     

Effects of triptolide on pharmacokinetics of fenofibrate in rats and its potential mechanism

1. Triptolide and fenofibrate are often used together for the treatment of nephrotic syndrome in Chinese clinics.

2. This study investigates the effects of triptolide on the pharmacokinetics of fenofibrate in rats and it potential mechanism.

3. The pharmacokinetics of fenofibrate (20?mg/kg) with or without triptolide pretreatment (2?mg/kg/day for seven days) were investigated. Additionally, the inhibitory effects of triptolide on the metabolic stability of fenofibrate were investigated using rat liver microsome incubation systems.

4. The results indicated that the C_max (35.34?±?7.52 vs. 30.43?±?6.45?μg/mL), t_1/2 (6.17?±?1.15 vs. 4.90?±?0.82?h) and AUC_(0–t) (468.12?±?35.84 vs. 416.35?±?32.68?mg?h?L^?1) of fenofibric acid decreased significantly (p?<?.05). The T_max of fenofibric acid increased significantly (p?<?.05) from 5.12?±?0.36 to 6.07?±?0.68?h. Additionally, the metabolic stability of fenofibrate was prolonged from 35.8?±?6.2 to 48.6?±?7.5?min (p?<?.05) with the pretreatment of triptolide.

5. In conclusion, these results indicated that triptolide could affect the pharmacokinetics of fenofibric acid, possibly by inhibiting the metabolism of fenofibrate in rat liver when they were co-administered.