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A highly sensitive liquid chromatography–tandem mass spectrometry (LC–MS–MS) method for the determination of troxerutin in human plasma using tramadol as internal standard (IS) has been developed and validated. Sample preparation involved liquid–liquid extraction with ethyl acetate–isopropanol (95:5, v/v). The analyte and IS were separated by RP–LC with gradient elution using 10 mM ammonium acetate containing 0.1% formic acid and methanol at a flow rate of 0.9 mL min−1. LC–MS–MS in the positive ion mode employed multiple reaction monitoring of the transitions at m/z 743.2→435.3 and m/z 264.1→58.0 for troxerutin and IS, respectively. The assay was linear in the concentration range 0.01–10 ng mL−1 with precision and accuracy within assay variability limits as per FDA guidelines. The assay was successfully applied to a pharmacokinetic study involving oral administration of 300 mg troxerutin to eight healthy Chinese volunteers.

Ethnopharmacological relevance Escin, a natural mixture of triterpene saponins, is commonly utilized for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema. Escin Ia is the chief active ingredient in escin and plays key role in mediating its pharmacological effects. Adequate pharmacokinetic data are essential for proper application of escin agent in clinical practice. However, pharmacokinetic properties of escin Ia are still poorly understood and this conflicts with the growing use of escin agent over the years. The goal of this study is to investigate the pharmacokinetic behavior of escin Ia in rats after low, medium and high-dose intravenous administration. Materials and methods Wistar rats were divided into 3 groups (n=6 per group) and escin Ia was administered via the caudal vein at doses of 0.5, 1.0 and 2.0 mg/kg, respectively. Subsequently, the concentrations of escin Ia and its metabolite isoescin Ia, a positional isomer of escin Ia, in rats׳ plasma were measured by an established liquid chromatography tandem mass spectrometry (LC–MS/MS) method at various time points following the administration of the drug. Main pharmacokinetic parameters were calculated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany). Results After intravenous administration, the Cmax and AUC of escin Ia increased in a dose-proportional manner at the dose of 0.5 mg/kg and 1.0 mg/kg, while increased in a more than dose-proportional manner at the doses of 1.0 mg/kg and 2.0 mg/kg. The t1/2 was significantly longer with increased intravenous doses, while other parameters such as CL and Vd also exhibit disagreement among three doses. Taken together, our data showed dose-dependent pharmacokinetic profile of escin Ia in rats after intravenous administration at the doses of 0.5–2.0 mg/kg. After intravenous administration, escin Ia was rapidly and extensively converted to isoescin Ia. Conclusions The results suggested dose-dependent pharmacokinetics of escin Ia at the doses of 0.5–2.0 mg/kg after intravenous administration. Escin Ia is isomerized to isoescin Ia rapidly and extensively regardless of the doses.

Escin Ia and isoescin Ia have been traditionally used clinically as the chief active ingredients of escin, a major triterpene saponin isolated from horse chestnut (Aesculus hippocastanum) seeds for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema.To establish a sensitive LC-MS/MS method and investigate the pharmacokinetic properties of escin Ia and isoescin Ia in rats and the pharmacokinetics difference of sodium escinate with pure escin Ia and isoescin Ia. The absolute bioavailability of escin Ia and isoescin Ia and the bidirectional interconversion of them in vivo were also scarcely reported.Wister rats were administrated an intravenous (i.v.) dose (1.7 mg/kg) of sodium escinate (corresponding to 0.5mg/kg of escin Ia and 0.5mg/kg of isoescin Ia, respectively) and an i.v. dose (0.5mg/kg) or oral dose (4mg/kg) of pure escin Ia or isoescin Ia, respectively. At different time points, the concentrations of escin Ia and isoescin Ia in rat plasma were determined by LC-MS/MS method. Main pharmacokinetic parameters including t(1/2), MRT, CL, V(d), AUC and F were estimated by non-compartmental analysis using the TopFit 2.0 software package (Thomae GmbH, Germany) and statistical analysis was performed using the Student's t-test with P0.05 as the level of significance.After administration of sodium escinate, the t(1/2) and MRT values for both escin Ia and isoescin Ia were larger than corresponding values for the compounds given alone. Absorption of escin Ia and isoescin Ia was very low with F values both0.25%. Escin Ia and isoescin Ia were found to form the other isomer in vivo with the conversion of escin Ia to isoescin Ia being much extensive than from isoescin Ia to escin Ia.Comparison of the pharmacokinetics of escin Ia and isoescin Ia given alone and together in rat suggest that administration of herbal preparations of escin for clinical use may provide longer duration of action than administration of single isomers. The interconversion of escin Ia and isoescin Ia when given alone indicates that administration of one isomer leads to exposure to the other.

Felbinac trometamol (trishydroxymethylaminomethane 4-biphenylacetate) is a new water-soluble salt of felbinac currently undergoing clinical evaluation as an intravenous (i.v.) formulation for the treatment of severe post-operative pain. This article reports the pharmacokinetics of felbinac after i.v. administration of felbinac trometamol in Sprague-Dawley rats. The maximum plasma concentration (C(0)) and area under the plasma concentration-time curve (AUC) of felbinac administered at doses of 3.36, 8.40 and 21.0 mg/kg felbinac trometamol increased linearly with dose. Felbinac was highly protein bound (~95%) at plasma concentrations up to 75 μg/ml and extensively metabolized with only small amounts being excreted unchanged in urine (0.318%), feces (0.530%) and bile (0.465%). 4'-Hydroxyfelbinac was the principal metabolite in urine, feces and bile together with felbinac glucuronide, 4'-hydroxyfelbinac glucuronide and sulfate. The majority of the administered dose was excreted in urine (63.6%) mostly as 4'-hydroxyfelbinac. Total drug in urine and feces accounted for about 72% of the dose. It would appear that felbinac trometamol has the potential to replace lipid-based NSAID formulations and progress to clinical evaluation.

A rapid and sensitive method for the simultaneous quantitation of hydrochlorothiazide (HCT) and metoprolol (MET) in human plasma based on liquid chromatography–tandem mass spectrometry (LC–MS/MS) has been developed and validated. MS/MS detection involved switching the electrospray ionization (ESI) mode during chromatography from negative to detect HCT and its internal standard (I.S.) 5-bromouracil to positive to detect MET and its I.S. tramadol. Sample preparation by liquid–liquid extraction with diethyl ether–dichloromethane (60:40, v/v) was followed by chromatography on a Venusil MP-C18 column using methanol–ammonium acetate (10 mM)–formic acid (pH 3.4) (50:50:0.05, v/v/v) at a flow rate of 0.8 mL/min. The method was linear in the concentration range 3–1000 ng/mL for both HCT and MET using 100 μL human plasma. Intra- and inter-day precisions (as relative standard deviation) for HCT were 2.9–3.9% and 3.9–4.7%, respectively and for MET were 2.4–4.1% and 4.7–6.2%, respectively. Accuracies (as relative error) were ±3.8% and ±2.6% for HCT and MET, respectively. The assay was successfully applied to a pharmacokinetic study involving a single oral dose of a combination tablet (25 mg HCT, 50 mg MET) in healthy volunteers.