This article aims to assess the bioequivalence of the test and the reference metformin hydrochloride tablets in healthy Chinese volunteers under fasting and fed conditions and to explore the effect of food on the pharmacokinetic (PK) profiles of both formulations. In total, 56 healthy Chinese subjects (28 in each group) were enrolled in this randomized, open, single-center, single-dose, 2-treatment, 2-sequence, 2-cycle cross clinical trial. The subjects were administrated a single dose of the test and the reference tablets at 0.25 g with a 7-day washout. Venous blood samples of all subjects were taken from predose 0 hour to postdose 24 hours according to the planned times. PK parameters for metformin were analyzed and calculated with noncompartmental methods. There were no significant differences in the PK parameters between the 2 formulations under both the fasting and the fed states. The 90% confidence intervals of 2 formulations were within 80.00%-125.00% based on C max , AUC 0-t , and AUC 0-∞ under both conditions. High-fat and high-calorie diets delayed the T max and reduced the AUC 0-t and AUC 0-∞. No severe adverse events occurred in this study. Two metformin hydrochloride tablets were bioequivalent under both fasting and fed states; the high-fat and high-calorie diet could lower the rate and extent of absorption of metformin in healthy Chinese volunteers.
A strategy for an integrated PK study based on chemiluminescence assays for cardiovascular herbal medicines with antioxidants as the main effective substances.
This paper reported a feasibility study strategy of identifying pharmacokinetic (PK) markers for a cardiovascular herbal medicine, Guanxin Danshen drop pill (GDDP). First, quantification analysis revealed the constituent composition in the preparation by high-performance liquid chromatography (HPLC). Subsequently, physiochemical property calculation predicted the solubility and intestinal permeability of the constituents in the preparation. Furthermore, HPLC–MS analysis ascertained the absorbable ingredients and their PK properties in rat plasma. The main effective substances from the ingredients absorbed into blood and their cardiovascular effects were also predicted by systems pharmacology study, and were further confirmed by in vivo protective effects on isoprenaline-induced myocardial injury in mice. Finally, the ingredients with high content, representative structure feature, favorable PK properties, high relevant degree to myocardial ischemia (MI) issues, and validated therapeutic effects were considered as the PK markers for the preparation. Ginsenosides Rg1, Rb1, and tanshinone (TS) IIA were identified originally as PK markers for representing PK properties of GDDP. In addition, integrated PK studies were carried out according to previous reports, viz. drug concentration sum method and the AUC weighting method, to understand the in vivo process of GDDP comprehensively. The present study maybe provide a reference approach to identify PK markers for cardiovascular herbal medicines.
Chrysocauloflavone I, an unfrequent biflavonoid, was purified from Selaginella doederleinii in this study. It showed cytotoxic effects on three human cancer cells, NCI-H1975, A549, and HepG-2, in vitro. In silico assessment of the physicochemical properties was performed for predicting the permeability and intestinal absorption of the tested compound. Subsequently, a rapid, sensitive, and specific high-performance liquid chromatography method was developed for determination of the compound in different biological samples to ascertain the pharmacokinetics, tissue distribution, and protein binding profiles of this active ingredient in rats. After intravenous dosing of chrysocauloflavone I at different levels (10 and 20 mg/kg), the elimination half-life was approximately 85 min, and the AUC0-∞ increased with the dose from 148.52 mg/L × min for 10 mg/kg to 399.01 mg/L × min for 20 mg/kg. After single intravenous dosing (20 mg/kg), chrysocauloflavone I was detected in all tissues studied with higher levels in the heart, blood, and lungs. The results of equilibrium dialysis indicated a very high protein binding degree (over 97%) for chrysocauloflavone I. After intragastric administration of 100 mg/kg chrysocauloflavone I to rats, no parent drug was detected in the rat plasma. This is the first report of the favorable bioactivities, plasma pharmacokinetics, tissue distribution, and protein binding profiles of the rare biflavone chrysocauloflavone I.
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