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Background and Objectives: Boswellic acids (BAs) include β-boswellic acid (BA), 3-acetyl-β-boswellic acid, 11-keto-β-boswellic acid, 3-acetyl-11-keto-β-boswellic acid, β-boswellic alcohol, and 3-acetyl-11-hydroxy-β-BA from Boswellia species, and are the main active ingredients of Boswellia serrata extracts (BSE). BSE have been used for the treatment of different inflammatory diseases; however, their pharmaceutical development has been severely limited by their poor oral bioavailability. The aims of this study were to investigate the molecular properties of six BAs, and to determine their experimental aqueous solubility, partition coefficient (Log P), gastrointestinal stability, adsorption-desorption kinetics, and permeability studies., Methods: The physicochemical properties of six BAs were obtained from SMILES representations using ChemDraw, and MarvinSketch. The molecular properties were also determined experimentally. The permeability studies were performed using parallel artificial membrane permeability assay (PAMPA), and Caco-2 cells., Results: The experimental Log P values of BAs correlated well (R 2  = 0.94) with the calculated Log P values. Metabolic stability data confirmed that BAs were found to be unstable in simulated gastrointestinal fluids and intestinal S9 fractions. The apparent permeability (P app ) range of BAs in both PAMPA and Caco-2 for the apical (AP) to basolateral (BL) was in the range of 0.52 ± 0.05 × 10 -6 to 2.84 ± 0.14 × 10 -6 cm/s. The efflux ratio of P app (BL → AP) to P app (AP → BL) for all BAs was < 2 in Caco-2 cells, suggesting greater permeability in the absorptive direction. Caco-2 cell adsorption studies confirmed the accumulation of BAs (35-55%) inside the enterocytes. These compounds exhibited a strong correlation between PAMPA and Caco-2 cell monolayer permeation data., Conclusions: The results of the present study have shown an empirical relationship between the molecular properties and intestinal absorption of BAs for the first time.

Background and Objectives: Astragaloside IV (AGS IV) is the most important bioactive constituent of Radix Astragali. However, its disappointing clinical application is mainly caused by its very low solubility in biologic fluids, resulting in poor bioavailability after oral administration. We recently obtained a novel water-soluble derivative of AGS IV (astragalosidic acid, LS-102) that displayed significant cardioprotective potential against hypoxia-induced injury. The objective of this study was to investigate the intestinal absorption, main pharmacokinetic parameters and acute toxicity of LS-102 in rodents compared with AGS IV., Methods: An oral dose of LS-102 and AGS IV (20 mg/kg) was administered to Sprague-Dawley (SD) rats, and blood samples were collected at predetermined time points. The plasma concentrations were detected by a validated UHPLC-MS/MS method, and pharmacokinetic parameters were calculated using a compartmental model. In the intestinal permeability study, the transport of LS-102 across Caco-2 cell monolayers was investigated at six concentrations from 6.25 to 250 µM. Moreover, the acute toxicity of LS-102 (40-5000 mg/kg) via a single oral administration was investigated in BALB/c mice., Results: LS-102 was rapidly absorbed, attaining a maximum concentration of 248.7 ± 22.0 ng/ml at 1.0 ± 0.5  h after oral administration. The relative bioavailability of LS-102 was twice that of AGS IV. LS-102 had a P app (mean) of 15.72-25.50 × 10 -6 cm/s, which was almost 500-fold higher than that of AGS IV, showing that LS-102 had better transepithelial permeability and could be better absorbed in the intestinal tract. The acute toxicity study showed no abnormal changes or mortality in mice treated with LS-102 even at the single high dose of 5000 mg/kg body weight., Conclusions: Oral LS-102 produced a pharmacokinetic profile different from AGS IV with higher bioavailability, while the toxic tolerance was similar to previous estimates. Thus, we speculated that LS-102 might provide better clinical efficacy and be a potential candidate for the new drug development of Radix Astragali.

Background and Objectives: Pristimerin has been reported to possess a wide range of pharmacological activities. This study investigates the effects of glycyrrhizic acid on the pharmacokinetics of pristimerin in rats., Methods: The pharmacokinetics of orally administered pristimerin (2 mg/kg) with or without glycyrrhizic acid pretreatment (at a dose of 100 mg/kg/day for 7 days) were investigated. The plasma concentration of pristimerin was determined using a sensitive and reliable LC-MS/MS method, and the pharmacokinetics profiles were calculated and compared. Additionally, Caco-2 cell transwell model and rat liver microsome incubation experiments were also conducted to investigate its potential mechanism., Results: The results showed that when the rats were pretreated with glycyrrhizic acid, the maximum concentration (C max ) of pristimerin decreased from 186.43 ± 14.18 to 124.62 ± 18.49 ng/mL, and area under the concentration-time curve from zero to infinity (AUC 0-inf ) also decreased from 918.54 ± 144.72 to 504.72 ± 115.63 μg·h/L. The elimination half-life (t 1/2 ) value of pristimerin decreased from 3.16 ± 1.18 to 1.88 ± 0.76 h (P < 0.05). The Caco-2 cell transwell experiments indicated that glycyrrhizic acid could increase the efflux ratio of pristimerin from 2.39 to 3.64, and the rat liver microsome incubation experiments showed that glycyrrhizic acid could significantly increase its intrinsic clearance rate from 51.87 ± 5.34 to 76.79 ± 8.52 µL/min/mg protein., Conclusions: In conclusion, these results indicated that glycyrrhizic acid could affect the pharmacokinetics of pristimerin, and it might work through decreasing the absorption of pristimerin by inducing the activity of P-gp or through increasing the clearance rate in rat liver by inducing the activity of cytochrome P450 enzyme.

Background and Objectives: Betulin is a triterpene extracted from the cork layer of the outer bark of Betula spp. It has a wide spectrum of pharmacological activities, including being lung protective; however, its bioavailability is low. To increase its bioavailability, betulin was entrapped in a nanosystem (BN). In this study, we investigated the pharmacokinetics and tissue distribution of nanosystem-entrapped betulin after single dose endotracheal administration to rats., Method: Betulin was nanosystem-entrapped using a solvent exchange technique. The surface morphology and size of the nanosystem were characterized by transmission electron microscopy and dynamic light scattering. The plasma and tissue concentrations of betulin were determined using a validated high-performance liquid chromatography method., Results: The highest concentration of betulin was found in lungs and liver, and the lowest in the heart. Betulin did not penetrate highly vascularized tissues or tissue with an average degree of vascularization, nor did it cross the blood-brain barrier. Tissue availability in the lungs was 1.3 times higher for BN than for free betulin. Betulin was detected in the bloodstream at 15 min after administration of BN compared with only at 1 h after administration of free betulin. Penetration of betulin in the liver tissue was characterized by a high degree of intensity both for BN and free betulin. Betulin in the heart tissue was detected in much smaller quantities than in the liver., Conclusion: Entrapment of betulin in nanosystem form shows promise as a novel strategy in the treatment of pulmonary diseases.

Yu-ping-feng decoction (YPF), a traditional Chinese medicine (TCM) prescription, is widely used to treat some respiratory tract diseases. This study was aimed to set up a pharmacokinetic-pharmacodynamic (PK-PD) model to assess dose-effect relationships for immunomodulatory effects of YPF in rats and to clarify compatibility mechanisms for TCM prescription system. Serum samples taken after YPF administration were tested on spleen cells of rats in vitro and proliferation ratio of spleen cells was used as end points to evaluate pharmacodynamic properties of immunoregulatory effects of YPF prescription. And with a HPLC-MS method, concentrations of Astragaloside IV (AS), a main component of YPF, were determined to achieve pharmacokinetic parameters after administration of a simplified prescription which is composed with AS, Atractylenolide I and Prim-O-glucosylcimifugin which are representative components of YPF. A plot of serum AS concentrations versus time and effects showed that there was a correlated relationship between AS concentrations and effects of YPF, and the concentration-response curve which was based on an E max model showed a counterclockwise hysteresis manner. A PK-PD model with Sheiner's method was used to describe time course of AS concentration in blood compartment and effect compartment, and main parameters with the PK-PD model were calculated. These results showed that there is a symmetry relationship between serum AS concentrations and responses of serum containing medicine of YPF prescription, which means that AS plays an important role in immunoregulatory effects of YPF. And the investigation on dose-effect relationships has displayed a feasible method to clarify mechanisms of combination for TCM prescriptions.

In this study, the pharmacokinetics of Astragaloside iv (AGS-IV) in Beagle dogs was studied by high performance liquid chromatography (HPLC) coupled with tandem mass spectrometry (MS). The concentrations of the drugs in plasma were determined after i.v. administration of 0.5, 1, 2 mg.kg(-1) AGS-IV and p.o. administration of 10 mg.kg(-1) AGS-IV. The areas under concentration-time curve (AUC) were linearly correlated to the doses administrated. The absolute bioavailability of AGS-IV after p.o. administration was found to be 7.4%. The plasma protein binding rate of AGS-IV was about 90% within a concentration range of 250-1000 ng.ml(-1). There was no significant species difference regarding the pharmacokinetics of AGS-IV between the rat and the Beagle dog.

Pharmacokinetics of Astragaloside IV (AGS-IV) in rats was studied by high performance liquid chromatography coupled with tandem mass spectrometry. The concentration in plasma was determined after i.v. administration of 1, 2, 4 mg/kg and p.o. administration of 20 mg/kg of AGS-IV. The AUC were linearly correlated to doses. Recoveries of AGS-IV in bile, urine and feces were also analyzed following i.v. dose of 2 mg/kg. Cumulative recovery of AGS-IV in bile reached 30.8% in 24h. Cumulative recovery of AGS-IV in urine and feces was 52.14%, which indicates that about 50% of AGS-IV was metabolized in vivo. The bioavailability of AGS-IV after p.o. administration was found to be 3.66%. These findings provide useful information for the research and development of AGS-IV and other potential agents.

The comparative steady-state bioavailability of asiatic acid was studied in 12 healthy male and female volunteers following oral administration of approximately equimolar doses of either asiatic acid (12 mg) or the glycoside derivative of asiatic acid, asiaticoside (24 mg). Both asiatic acid and asiaticoside are constituents of the marketed dermatological product Madecassol. Asiaticoside is converted in vivo to asiatic acid by hydrolytic cleavage of the sugar moiety. Steady-state AUC0-12h values for asiatic acid on either regimen were similar (614 +/- 250 ng.h/ml following asiatic acid compared to 606 +/- 316 ng.h/ml following asiaticoside) indicating comparable bioavailability for asiatic acid with the two ingredients at approximately equimolar doses. Since asiatic acid is considered to be the most therapeutically active ingredient of Madecassol, the current data suggest that the therapeutic effects of asiaticoside may be mediated through conversion to asiatic acid.