Pharmacokinetics, tissue distribution, and excretion study of GL-V9 and its glucuronide metabolite 5-O-glucuronide GL-V9 in Sprague-Dawley rats.

The objective of this study is to explore the pharmacokinetics, tissue distribution, and excretion patterns of GL-V9 and its glucuronide metabolite, 5-O-glucuronide GL-V9, following the administration of GL-V9 to Sprague-Dawley (SD) rats. In this research, we developed and validated rapid, sensitive, and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) methods for quantifying GL-V9 and 5-O-glucuronide GL-V9 in various biological samples, including SD rat plasma, tissue homogenate, bile, urine, and feces. Quantification of GL-V9 and 5-O-glucuronide GL-V9 in plasma, tissue homogenate, bile, urine, and feces was performed using the validated LC-MS/MS methods. The bioavailability of GL-V9 in SD rats ranged from 6.23% to 7.08%, and both GL-V9 and 5-O-glucuronide GL-V9 exhibited wide distribution and rapid elimination from tissues. The primary distribution tissues for GL-V9 and 5-O-glucuronide GL-V9 in rats were the duodenum, liver, and lung. GL-V9 was predominantly excreted in urine, while 5-O-glucuronide GL-V9 was primarily excreted in bile. GL-V9 exhibited easy absorption and rapid conversion to its glucuronide metabolite, 5-O-glucuronide GL-V9, following administration.

Trace quantification of GL-V9 and its glucuronide metabolites (5-O-glucuronide GL-V9) in Beagle dog plasma by UPLC-MS/MS and its application to a pharmacokinetic study.

GL-V9, a new synthetic flavonoid derived from wogonin, has shown beneficial biological functions. In this study, accurate and sensitive UPLC-MS/MS methods were developed and validated for the quantification of GL-V9 and its glucuronide metabolite (5-O-glucuronide GL-V9) in Beagle dog plasma. The chromatographic separation was performed on a C8 column (ACE Excel 5 C8 50×3.0 mm) using 0.1% formic acid and acetonitrile were used as mobile phase. Mass detection was performed on a triple quadrupole tandem mass spectrometer equipped with an electrospray ionization (ESI) interface operating in positive ion mode. Quantitative analysis was performed in multiple reaction monitoring (MRM) mode with the transitions of m/z 410.2→126.1 for GL-V9, m/z 586.3→410.0 for 5-O-glucuronide GL-V9 and m/z 180.0→110.3 for phenacetin (internal standard), respectively. The calibration curves for GL-V9 and 5-O-glucuronide GL-V9 showed excellent linearity over the concentration range of 0.5-500 ng/mL with correlation coefficient greater than 0.99. The intra- and inter-day accuracies were within 99.86% to 109.20% for GL-V9 and 92.55% to 106.20% for 5-O-glucuronide GL-V9, respectively. The mean recovery was 88.64% ± 2.70% for GL-V9, and 92.31% ± 6.28% for 5-O-glucuronide GL-V9, respectively. The validated method was successfully applied to the pharmacokinetic study in Beagle dogs after oral and intravenous administration. The oral bioavailability of GL-V9 was approximately 2.47%~4.35% in Beagle dogs and reached steady state on the fifth day after repeated dosing.

Comparison of three water-soluble polyphosphate tripolyphosphate, phytic acid, and sodium hexametaphosphate as crosslinking agents in chitosan nanoparticle formulation.

Chitosan nanoparticles (CS-NPs) prepared by ionic gelation with tripolyphosphate (TPP) are a promising drug carrier for mucosal administration due to their remarkable mucoadhesivity and biocompatibility. In this work, CS-NPs were obtained by an ionotropic gelation method with polyphosphate crosslinking agents of tripolyphosphate (TPP), phytic acid (PA), and sodium hexametaphosphate (SHMP). The drug encapsulation efficiency, in vitro drug release behavior, mucoadhesivity, and cytotoxicity of the CS-NPs were evaluated. The results demonstrated that the high concentration of H+ ion would impede the formation of CS-TPP-NPs but promote the formation of CS-PA-NPs and CS-SHMP-NPs. The obtained CS-NPs were approximately spherical in shape, biocompatible confirmed by the cytotoxicity test, and bioadhesive particles with a narrow diameter distribution (0.20 ±â€¯0.02 of polydispersity index) less than 200 nm. The encapsulation efficiency of myricetin (MYR) in CS-NPs crosslinked by PA and SHMP (67.3 ±â€¯0.4 % and 62.2 ±â€¯0.2 %) was significantly higher than that in CS-NPs crosslinked by TPP (47.7 ±â€¯0.1 %) (p < 0.05); their drug release rate (43.7 ±â€¯5.1 % and 44.0 ±â€¯3.7 %) was also significantly slower than that of MYR-CS-NPs crosslinked by TPP (103.4 ±â€¯4.0 %) (p < 0.05). Furthermore, a strong mucoadhesiveness of the CS-NPs crosslinked by PA was shown by a fast increase of the turbidity value and a sharp decrease of the zeta potential in the mucin solution test.

Development of daidzein nanosuspensions: Preparation, characterization, in vitro evaluation, and pharmacokinetic analysis.

The purpose of this investigation was to improve the solubility and oral bioavailability of daidzein via preparing nanosuspensions (NS) with steric stabilizers, electrostatic stabilizers, or a combination of both. Based on particle size and zeta potential, daidzein NS stabilized by HP-ß-CD, soy lecithin, HP-ß-CD + soy lecithin, TPGS, TPGS + SBE-ß-CD, SDS, or HPMC E5 + SDS were generated and characterized by scanning electron microscopy, powder X-ray diffraction, and Fourier transform-infrared spectroscopy. In addition, the stability, cytotoxicity, solubility, dissolution, and pharmacokinetics of NS were evaluated. The resulting daidzein NS were physically stable and biocompatible and presented as regular shapes with homogenous particle sizes of 360-600 nm and decreased crystallinity. Due to the increased solubility and dissolution rate, the oral bioavailability of daidzein NS in rats was 1.63-2.19 times greater than that of crude daidzein. In particular, among the investigated seven daidzein NS formulations, daidzein NS prepared with the costabilizers HPMC E5 + SDS is an optimal formulation for increased daidzein bioavailability. The present study proposes that the combined usage of steric and electrostatic stabilizers is a promising strategy for improving the bioavailability of water-insoluble flavonoid compounds by an NS approach.