Effects of polymer molecular weight on relative oral bioavailability of curcumin.

BACKGROUND: Polylactic-co-glycolic acid (PLGA) nanoparticles have been used to increase the relative oral bioavailability of hydrophobic compounds and polyphenols in recent years, but the effects of the molecular weight of PLGA on bioavailability are still unknown. This study investigated the influence of polymer molecular weight on the relative oral bioavailability of curcumin, and explored the possible mechanism accounting for the outcome. METHODS: Curcumin encapsulated in low (5000-15,000) and high (40,000-75,000) molecular weight PLGA (LMw-NPC and HMw-NPC, respectively) were prepared using an emulsification-solvent evaporation method. Curcumin alone and in the nanoformulations was administered orally to freely mobile rats, and blood samples were collected to evaluate the bioavailability of curcumin, LMw-NPC, and HMw-NPC. An ex vivo experimental gut absorption model was used to investigate the effects of different molecular weights of PLGA formulation on absorption of curcumin. High-performance liquid chromatography with diode array detection was used for quantification of curcumin in biosamples. RESULTS: There were no significant differences in particle properties between LMw-NPC and HMw-NPC, but the relative bioavailability of HMw-NPC was 1.67-fold and 40-fold higher than that of LMw-NPC and conventional curcumin, respectively. In addition, the mean peak concentration (C(max)) of conventional curcumin, LMw-NPC, and HMw-NPC was 0.028, 0.042, and 0.057 µg/mL, respectively. The gut absorption study further revealed that the HMw-PLGA formulation markedly increased the absorption rate of curcumin in the duodenum and resulted in excellent bioavailability compared with conventional curcumin and LMw-NPC. CONCLUSION: Our findings demonstrate that different molecular weights of PLGA have varying bioavailability, contributing to changes in the absorption rate at the duodenum. The results of this study provide the rationale for design of a nanomedicine delivery system to enhance the bioavailability of water-insoluble pharmaceutical compounds and functional foods.

Isolation of gentiopicroside from Gentianae Radix and its pharmacokinetics on liver ischemia/reperfusion rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Gentiopicroside (GPS) is a secoiridoid glucoside isolated from the ethanol extract of Gentianae Radix with a content of 13%, which has been used for centuries in Chinese as a digestive aid. AIM OF THE STUDY: This study investigates the pharmacokinetics of GPS and its metabolic pathway for the liver ischemia/reperfusion (I/R) in rats. MATERIALS AND METHODS: The experimental animals were anesthetized intraperitoneally (i.p.) with a mixture of urethane (1.0 g/kg) and α-chloralose (0.1 g/kg). A midline laparatomy was performed and the liver hilum was gently exposed. All structures in the portal triad (hepatic artery, portal vein, and bile duct) to the left and median liver lobes were occluded with silk thread for 30 min. Ischemia was followed by a sudden reperfusion after removing the occluding threads. After 60 min reperfusion, the rats received a single intravenous 5 mg/kg dose of GPS. RESULTS: The area under concentration curve (AUC) was significantly increased; however, the clearance (Cl) was significantly decreased in the liver I/R rats. Furthermore, after pretreated with SKF-525A (50 mg/kg, i.p.), a cytochrome P450 (CYP) inhibitor, AUC, elimination half-life (t(1/2)) and the mean residence time (MRT) of GPS in rat blood were significantly increased, suggesting that CYP was involved in the metabolism of GPS. For the group without liver I/R, GPS was administered at doses of 5 mg/kg and 100 mg/kg intravenously and orally, respectively. The pharmacokinetic results indicated that the AUC was 565±95.1 and 1163±273 min µg/mL and the t(1/2) of GPS was 71±9 and 106±17 min after intravenous and oral administration, respectively. The oral bioavailability of GPS was 10.3±2.4% in the rats. CONCLUSIONS: The status of I/R might prolong the disposition of GPS, and the plasma concentration of GPS in the liver I/R injury rats was significantly increased. The increased body exposure of GPS in the treatment of liver I/R may result from the decreased metabolism of GPS mediated by CYP in the liver.

Pharmacokinetic Studies of Chinese Medicinal Herbs Using an Automated Blood Sampling System and Liquid Chromatography-mass Spectrometry.

The safety of herbal products is one of the major concerns for the modernization of traditional Chinese medicine, and pharmacokinetic data of medicinal herbs guide us to design the rational use of the herbal formula. This article reviews the advantages of the automated blood sampling (ABS) systems for pharmacokinetic studies. In addition, three commonly used sample preparative methods, protein precipitation, liquid-liquid extraction and solid-phase extraction, are introduced. Furthermore, the definition, causes and evaluation of matrix effects in liquid chromatography-mass spectrometry (LC/MS) analysis are demonstrated. Finally, we present our previous works as practical examples of the application of ABS systems and LC/MS for the pharmacokinetic studies of Chinese medicinal herbs.

Curcumin and its nano-formulation: the kinetics of tissue distribution and blood-brain barrier penetration.

Curcumin has considerable neuro-protective and anti-cancer properties but is rapidly eliminated from the body. By optimizing the HPLC method for analysis of curcumin, this study evaluates how the ability of curcumin to penetrate organs and different regions of the brain is affected by nanoparticulation to increase curcumin circulation time in the body. Curcumin-loaded PLGA nanoparticles (C-NPs) were prepared by the high-pressure emulsification-solvent evaporation method. The mean particle size and entrapment efficiency were 163nm and 46.9%, respectively. The release profile of C-NPs was an initial burst effect followed by sustained diffusion. In distribution studies, curcumin could be detected in the evaluated organs, including liver, heart, spleen, lung, kidney and brain. C-NPs were found mainly in the spleen, followed by the lung. Formulation significantly raised the curcumin concentration in these organs with increases in the AUC, t(1/2) and MRT of curcumin, though this was not apparent in the heart. Curcumin and C-NPs could cross the blood-brain barrier (BBB) to enter brain tissue, where it was concentrated chiefly in the hippocampus. Nanoparticulation significantly prolonged retention time of curcumin in the cerebral cortex (increased by 96%) and hippocampus (increased by 83%). These findings provide further understanding for the possible therapeutic effects of curcumin and C-NPs in further pre-clinical and clinical research.

Biological analysis of herbal medicines used for the treatment of liver diseases.

Herbal medicines have been used to treat liver disorders for thousands of years in the East and have now become a promising therapy internationally for pathological liver conditions. Biological analysis of hepatoprotective herbs is an important issue from the pharmacokinetic perspective in developing new therapeutic managements for liver disease. The biological analysis focuses on the pretreatment methods, separation and quantification of herbal medicines in biological samples. We have compiled and discuss the biological analytical method of six herbal medicines for liver protection containing Silybum marianum(silymarin), Glycyrrhiza glabra, Scutellaria baicalensis, Schisandra chinensis, Salvia miltiorrhiza and Astragalus membranaceus. This review provides a convenient reference for researchers to reduce time-consuming method optimization.

Optimised nano-formulation on the bioavailability of hydrophobic polyphenol, curcumin, in freely-moving rats.

This study has optimised the poly lactic-co-glycolic acid (PLGA) nano-formulation of curcumin to prolong its retention time in the body and improve bioavailability. High-pressure emulsification-solvent-evaporation was designed to obtain curcumin-loaded PLGA nanoparticles (C-NPs) prepared with 2% of PVA containing 20% sucrose as aqueous phase and dichloromethane as oil phase. The size and entrapment efficiency of C-NPs was 158±10nm and 46.6±13.5%, respectively. The stable storage time of C-NPs was one month at 4°C. When curcumin was formulated, a significant increase of curcumin exposure in rat plasma was revealed from the intravenous study (AUC/Dose raised 55%) and the oral study (AUC/Dose increased 21-fold). The oral bioavailability of curcumin at C-NPs was 22-fold higher than conventional curcumin. Excretion results support oral study that absorption of curcumin was significantly increased by nano-formulation. These findings demonstrate that PLGA nano-formulation could potentially be applied to increase bioavailability of hydrophobic polyphenols.

Herb-drug interaction of Andrographis paniculata extract and andrographolide on the pharmacokinetics of theophylline in rats.

Herb-drug interaction has become a serious problem since herbal medicine is extensively used in the modern world. This study investigates effects of Andrographis paniculata extract (APE) and its major component, andrographolide (AG), on the pharmacokinetics of theophylline, a typical substrate of cytochrome P450 1A2 enzyme, in rats. After APE or AG pretreatment for 3 days, on the fourth day rats were administered theophylline via femoral vein cannula. The blood theophylline levels were monitored by microdialysis sampling combined with HPLC-UV. The results indicated that the clearance of theophylline was significantly increased and the area under concentration-time curve (AUC) was reduced in both AG and APE pretreated groups at low-dose theophylline administration (1mg/kg). The elimination half-life (t(1/2beta)) and mean residence time (MRT) of theophylline were shortened by 14% and 17%, respectively, in the AG pretreated group when high-dose theophylline (5mg/kg) was given. However, theophylline accumulated in rat of the group with APE pretreatment. This phenomenon suggests that some other herbal components contained in APE may interact with theophylline and retard its elimination when theophylline was administered at a high dose. Our results suggest that patients who want to use CYP1A2-metabolized drugs such as caffeine and theophylline should be advised of the potential herb-drug interaction, to reduce therapeutic failure or increased toxicity of conventional drug therapy.