Visible-light-mediated photocatalytic cross-coupling of acetenyl ketones with benzyl trifluoroborate.

In this report, we describe a simple visible light-triggered Barbier-type reaction by employing acetenyl ketones with benzyl trifluoroborates. Through a radical-radical cross-coupling process, this photocatalytic protocol furnished a wide range of tertiary propargyl alcohols. Mechanistic investigation indicated that proton-coupled electron transfer (PCET) might be involved in the photochemical transformations.

[Intestinal absorption properties of ponicidin by single pass perfusion model in rats].

To determine the absorption properties and study the intestinal absorption kinetics of poncidin in rats. In situ single pass perfusion model was combined with High Performance Liquid Chromatography-Mass Spectrometry (HPLC-MS/MS) method to investigate the intestinal absorption characteristics and calculate absorption parameters with aspects of drug absorption, concentration and perfusion medium. The absorption of poncidin under acid condition at pH 6.5 was more stable, where intestinal enzymes showed little influence on metabolism, and the absorption was significantly higher than that in pH alkaline condition at pH 8.0 (P<0.05). Drug concentrations had no significant influence on absorption rate constant of the same intestinal segment Ka and apparent permeability coefficient Papp values of poncidin. Different concentrations of poncidin showed no significant differences in the Ka and Papp values among duodenum, jejunum and colon, but the values were significantly lower than ileum absorption parameters, with significant differences (P<0.05). There was no significant effect of verapamil on intestinal absorption of poncidin. The results showed that poncidin could be absorbed at all the studied intestinal segments while ileum seemed to be the best absorption segment in the concentration range of 10-1 000 µg·L⁻¹. The absorption was characterized by a linear dynamic process of passive transport, without absorption saturation. Weak acid environment was helpful for the intestinal absorption of poncidin, and ponicidin was not a substrate of P-glycoprotein (P-gp).

[Interaction and mechanism between poinicidin and BSA].

To establish a sensitive and specific LC-MS/MS method for determination of the binding conditions of ponicidin with bovine serum albumin (BSA) and analysis of its mechanism. The protein binding rates and related binding constants of ponicidin in BSA samples were determined by ultrafiltration and LC-MS/MS. Scatchard equation was used to calculate the binding constant (Ka) of ponicidin in BSA samples as well as the number of binding sites (n), and the mechanism on ponicidin binding with BSA was explored. The results showed that the average protein binding rate of ponicidin with BSA was 57.2%, mainly as grade Ⅰ intensive binding, and the relevant binding constant was 2.54×104 L•µg⁻¹, with a binding site number of n=0.75. The binding of ponicidin with BSA had no concentration dependence within the investigated concentrations. The established method in this study showed high sensitivity, specificity, simple operation and met the analysis requirements, and the calculation of binding constant laid foundation for the clinical drug interactions and pharmacokinetics research.

LC-MS-MS for the determination of ponicidin in dog plasma.

A highly specific and sensitive liquid chromatography-tandem mass spectrometry method has been developed and validated for the determination of ponicidin in dog plasma. The plasma samples were prepared using liquid-liquid extraction with ethyl acetate as the extraction solvent. Chromatographic separation was accomplished on a Waters XTerra MS C18 column. The extracted ponicidin and the internal standard, oridonin, were detected by tandem mass spectrometry in positive electrospray ionization mode with multiple reaction monitoring. The optimized mass transition ion pairs (m/z) for quantitation were 363.08-345.08 for ponicidin and m/z 365.10-347.06 for the internal standard. The lower limit of quantification was 5 ng/mL. The linear range of the method was from 5 to 5,000 ng/mL. The intra-day and inter-day precision measurements were lower than 5.3 and 6.0% in terms of relative standard deviation and the accuracy was within ±8.4% in terms of relative error. Additionally, no significant matrix ionization suppression or enhancement was observed. The validated method was successfully applied in a pharmacokinetic study of ponicidin in dogs. The primary pharmacokinetic parameters in dogs were: terminal elimination half-life, 8.14 ± 1.35 h; mean residence time, 12.30 ± 2.08 h; area under the plasma concentration-time curve from time zero to the last measurable concentration, 14.34 ± 1.37 µg/h/mL; area under the plasma concentration-time curve from time zero to infinity, 15.75 ± 1.44 µg/h/mL; apparent volume of distribution, 4.79± 1.68 L/kg; total body clearance, 0.41 ± 0.08 L/kg/h.

Pharmacokinetic study of Guanfu base G in rats by LC-ESI-MS.

A sensitive and simple liquid chromatography -: electrospray ionization mass spectrometry method has been established and validated for the quantification of Guanfu base G in rats. Phenoprolamine hydrochloride was selected as the internal standard. Sample preparation involved simple liquid-liquid extraction by ethylacetate with high efficiency. The chromatographical separation was performed on a Shimadzu C18 column (150 × 2.0 mm, 5 µm) with a gradient elution of 0.2% acetic acid-acetonitrile (30:70, v/v). The method was sensitive with the lowest limit of detection at 1 ng/mL (S/N ≥ 3) in 100 µL of rat plasma. Good linearity (r = 0.9996) was obtained covering a concentration of 5-2000 ng/mL. The intra- and interday assay precision ranged from 4.3 to 6.1% and 5.4 to 8.3%, respectively. In addition, the stability, extraction recovery and matrix effect involved in the method were also validated. After intravenous dosing, rat plasma Guangfu base G (GFG) concentration declined in a biphasic manner with a terminal elimination half-life of 3.72 h. The total plasma clearance values were 1.15 L/h/kg. After oral dosing, the plasma GFG concentration reached a maximum within 0.5 h. The absolute bioavailability of GFG was 83.06%.

Determination of antazoline hydrochloride in rat plasma and excreta by reversed-phase ion-pair chromatography and its application to pharmacokinetics.

A reversed-phase ion pair chromatography method with liquid-liquid extraction analytical method was developed and validated for the determination of antazoline hydrochloride in plasma and excreta of rat. The aim of our study was to characterize the preclinical pharmacokinetics and excretion profiles of antazoline hydrochloride in rats after intravenous injection at the dose of 10 mg/kg. Plasma and excreta samples were extracted with ethyl acetate, and phenacetin was used as the internal standard. The result showed that the method is suitable for the quantification of antazoline hydrochloride in plasma and excreta samples. Analysis of accuracy (90.89-112.33%), imprecision (<7.1%) and recovery (>82.5%) showed adequate values. After a single intravenous administration at 10 mg/kg to rats, plasma concentration profile showed a relative fast elimination proceeding with a terminal elimination half-life of 3.53 h. Approximately 61.8 and 14.2% of the administered dose were recovered in urine and bile after 72 and 24 h post-dosing respectively; 5.9% of the administered dose was recovered in feces after 72 h post-dosing. The above results show that the major elimination route is urinary excretion.

Determination of antazoline hydrochloride in Beagle dog plasma by HPLC-UV and its application to pharmacokinetics.

In order to evaluate the pharmacokinetics characteristic of antazoline hydrochloride in Beagle dogs, a sensitive and specific HPLC method was developed and validated using phenacetin as the internal standard (IS). The analyte and the IS were extracted from dog plasma by ethyl acetate under the basic condition. The analyte was separated by a C18 column and detected with a variable wavelength UV-detector. The mobile phase consisted of methanol-5mmolL(-1) tetrabutyl ammonium bromide (45:55, v/v) containing 0.5% glacial acetic acid in a flow rate of 1.0mLmin(-1). Standard calibration graph for antazoline was linear over a curve range of 20-1600ngmL(-1) (R>0.99) and the lower limit of quantification was 20ngmL(-1) using a plasma sample of 500µL. The intra- and inter-day precision values were less than 14.3% relative standard deviation (RSD). The intra-day assay accuracy was in the range of 98.1-100.6% and the inter-day assay accuracy in the range of 99.2-101.1%. The extraction recoveries were on the average of 88.4% for antazoline and 76.8% for IS. Plasma samples were stable at least for 1 month at -20°C. This method was successfully applied to pharmacokinetics study of antazoline after intravenous administration to Beagle dogs.