ABSTRACT
A fast and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of prodrug of paclitaxel (Pro-PTX) and paclitaxel (PTX) in rat plasma was developed. The plasma samples were subjected to protein precipitation with acetonitrile (0.1% formic acid), and then separated by LC with an Ultimate AQ-C18 column (50 mm × 3.0 mm, 3 μm) and acetonitrile-1 mmol·L-1 ammonium formate (containing 0.1% formic acid) as the mobile phase. Multiple reaction monitoring (MRM) scanning mode was used to detect the ion responses m/z 983.4→415.2 (Pro-PTX), m/z 854.4→286.1 (PTX) and m/z 808.3→527.2 (Docetaxel, internal standard) by using a triple quadrupole tandem mass spectrometer with electrospray ionization source and positive ion mode. The method validation results show that the linear ranges of Pro-PTX and PTX in plasma were 2.00-500 ng·mL-1 (r > 0.99) and 4.00-1 000 ng·mL-1 (r > 0.99), the lower limit of quantification was 2.00 ng·mL-1 and 4.00 ng·mL-1, respectively; the quality control samples with low, medium and high concentrations of Pro-PTX and PTX were within the batch, the relative standard deviation (RSD) between batches were all less than 9%; the relative deviation (RE) was within the range of ± 9%; In the stability test, both Pro-PTX and PTX in plasma were stable under various storage conditions. The method was sensitive, specific, and reproducible, and was suitable for the pharmacokinetic study of Pro-PTX in rats. Animal experiments were approved by the Ethics Committee of Laboratory Animal Management and Animal Welfare, Institute of Materia Medica, Chinese Academy of Medical Sciences (No.: 00003552).
ABSTRACT
Objective: The study was designed to prepare Nano-sponge formulation loaded with nifedipine. Studying parameters which affecting the formulas in addition to pharmacokinetics and toxicity tests. Methods: Nine Nano-sponge formulations were prepared by the solvent evaporation technique. Different ratios of polymer ethylcellulose, CO-polymers β-cyclodextrin and hydroxypropyl β-cyclodextrin in addition to solubilizing agent polyvinyl alcohol were used. Thermal analysis, X-ray powder diffraction (XRPD), shape and surface morphology, particle size, %production yield, %porosity, % swelling, and % drug entrapment efficiency of Nano-sponge were examined. Release kinetic also studied beside comparison of pharmacokinetic parameters of the optimum choice formula and marketed one in addition to Toxicological consideration. Results: Particle size in the range of 119.1 nm to 529 nm which were increased due to the increase in the concentration of polymer to the drug. Nano-sponge revealed porous, spherical nature. Increased in the drug/polymer molar ratios (1:1 to 1:3) may increase their % production yield ranged from 62.1% to 92.4%. The drug content of different formulations was in the range of 77.9% to 94.7%, and entrapment efficiency was in the range of 82.72 % to 96.63%. Drug released in controlled sustained pattern and followed Higuchi, s diffusion mechanism. Pharmacokinetic parameters of optimized formula showed significant higher maximum plasma drug concentration, area under plasma concentration-time curve, volume of distribution and mean residence time. Nano-sponge loaded drug proved biological safety at low concentrations. Conclusion: Nano-sponge drug delivery system has showed small Nano size, porous with controlled drug release and significant-high plasma drug concentration that improved solubility, drug bioavailability and proved safety.
ABSTRACT
The purpose of this article was to study the pharmacokinetic characteristics of YZG-331, plasma protein binding and metabolic stability in vivo and in vitro. Plasma and tissue concentrations of YZG-331 were determined in mice and rats after administration by LC-MS/MS analysis orally or intravenously. The plasma protein binding of YZG-331 with human, dog, monkey, rat and mouse were measured by ultrafiltration method. The stability of YZG-331 in animal and human plasma, liver microsomes, intestinal bacteria and artificial gastrointestinal fluid was also investigated in vitro. The results show that YZG-331 was absorbed rapidly in both mice and rats after oral administration, while the absorption and elimination saturation YZG-331 were also observed. The bioavailability of YZG-331 was much higher in male mice (51.2%) than that in female mice (27.7%), however, the bioavailability in male rats (27.1%) was lower than that in female rats (78.7%). YZG-331 was widely distributed in different tissues of mice, especially in certain regains of brain, including thalamus, hippocampi, cortical and striatal. YZG-331 was found to bind to human, dog, monkey, rat and mouse plasma protein in vitro (93.3%-98.9%) without significant concentration dependences and species differences. YZG-331 was stable in animal and human plasma, simulated gastric/intestinal fluid and liver microsomal incubations, except rat liver microsomes and intestinal flora. Therefore, we concluded that:the pharmacokinetics of YZG-331 in mice and rats have gender and species differences; YZG-331 was widely distributed in vivo including brain, the targets of the agent; YZG-331 had a high affinity to plasma protein and was metabolized by rat liver microsomes and intestinal flora.