Determination of cefoperazone and sulbactam in serum by HPLC-MS/MS: An adapted method for therapeutic drug monitoring in children.

A rapid, accurate and specific high-performance liquid chromatography-tandem mass spectrometry method has been validated for the simultaneous determination of cefoperazone and sulbactam in a small volume sample for children. A Shim-pack XR-ODS C18 column with gradient elution of water (0.1% formic acid) and acetonitrile (0.1% formic acid) solution was used for separation at a flow rate of 0.3 mL/min. The calibration curves of two analytes in serum showed excellent linearity over the concentration ranges of 0.03-10 µg/mL for cefoperazone, and 0.01-3 µg/mL for sulbactam, respectively. This method involves simple sample preparation steps and was validated according to standard US Food and Drug Administration and European Medicines Agency guidelines in terms of selectivity, linearity, detection limits, matrix effects, accuracy, precision, recovery and stability. This assay can be easily implemented in clinical practice to determine concentrations of cefoperazone and sulbactam in children.

Effects of Polymorphisms in NR1H4, NR1I2, SLCO1B1, and ABCG2 on the Pharmacokinetics of Rosuvastatin in Healthy Chinese Volunteers.

The nuclear receptors (NR)-farnesoid X receptor (FXR, NR1H4) and pregnane X receptor (PXR, NR1I2)-have important effects on the expression of genes related to the pharmacokinetics (PKs) of rosuvastatin. This study was designed to investigate whether the genetic variants in drug disposition genes (SLCO1B1 and ABCG2) combined with their upstream regulators (NR1H4 and NR1I2) would affect the PKs of rosuvastatin in a Chinese population. Sixty-one healthy male volunteers were enrolled and the plasma concentrations of rosuvastatin were measured using the liquid chromatographic-tandem mass spectrometry/MS method. All subjects were analyzed and grouped according to the genotypes of NR1H4, NR1I2, SLCO1B1, and ABCG2. The exposure of rosuvastatin was higher in subjects carrying the SLCO1B1 521C or ABCG2 421A allele compared with noncarriers. No association was observed of single-nucleotide polymorphisms in NR1H4 or NR1I2 genes with the PKs of rosuvastatin. After adjusting for the 421C>A and 521T>C variants, the Cmax in subjects with NR1I2 63396TT wild type were about 2-fold of those of NR1I2 mutant type (63396CC and CT) (10.7 vs. 20.4 ng/mL, P = 0.023), whereas no significant differences were observed for other parameters. Polymorphisms investigated in the genes of NR1H4 and NR1I2 seemed to play no significant role in the disposition of rosuvastatin.

Pharmacokinetics of escin Ia in rats after intravenous administration.

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.

Comparative pharmacokinetics and the bioavailability of escin Ib and isoescin Ib following the administration of escin, pure escin Ib and isoescin Ib in rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Adequate pharmacokinetic data of escin, a natural mixture of triterpene saponins used for the treatment of chronic venous insufficiency, hemorrhoids, inflammation and edema, is of special interest in view of the growing use of escin agent in clinical medicine. However, pharmacokinetic data are inadequate to support their clinical indication. Escin Ib and isoescin Ib are the chief active ingredients in escin, pharmacokinetics study of them would be helpful for improving the practice of escin application. The goals of this study are to determine the plasma concentration of escin Ib and isoescin Ib using an established liquid chromatography tandem mass spectrometry (LC-MS/MS) method and to compare the pharmacokinetics and bioavailability of these compounds in rats when administered as pure isomers or as sodium escinate. MATERIALS AND METHODS: Five groups of Wistar rats (n=6 per group) were treated with either an intravenous (IV) dose (2.78mg/kg) of sodium escinate (corresponding to 0.5mg/kg of escin Ib and 0.5mg/kg of isoescin Ib), an IV dose (0.5mg/kg) and an oral dose (4mg/kg) of pure escin Ib or isoescin Ib. The concentrations of escin Ib and isoescin Ib in rat plasma were determined by LC-MS/MS at various times following the administration of the drugs. The pharmacokinetic parameters were estimated by a non-compartmental analysis and then subjected to statistical analysis. RESULTS: The administration of sodium escinate, which contains the two isomers, gave rise to higher terminal phase half-life (t1/2) and mean residence time (MRT) values for both escin Ib and isoescin Ib compared to the corresponding compounds administered alone. The absorption of escin Ib and isoescin Ib was very poor, with the oral bioavailability (F) values of <2% observed for both compounds. The two compounds were found to isomerize in vivo, wherein the conversion of escin Ib to isoescin Ib was much easier than that of isoescin Ib to escin Ib. CONCLUSIONS: A comparison of the pharmacokinetics of escin Ib and isoescin Ib administered alone and together in rats suggests that the administration of herbal preparations of escin in a clinical setting may result in a longer duration of action than the administration of each isomer alone. The interconversion of escin Ib and isoescin Ib when administered alone indicates that the administration of one isomer results in exposure to the other isomer.

Comparative pharmacokinetics and bioavailability of escin Ia and isoescin Ia after administration of escin and of pure escin Ia and isoescin Ia in rat.

ETHNOPHARMACOLOGICAL RELEVANCE: 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. AIM OF THE STUDY: 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. MATERIALS AND METHODS: 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 P<0.05 as the level of significance. RESULTS: 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 both <0.25%. 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. CONCLUSION: 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.

[Study of pharmacokinetics of nicotine in local brain by using microdialysis and stable labeled isotope].

The paper is to report the study of pharmacokinetics of transdermal administered nicotine in the brain of freely moving rat by using microdialysis with stable labeled isotope as internal standard. The pharmacokinetic behavior of nicotine in Sprague Dawley rat brain was investigated after intranasal administration (3.75 mg). Brain fluid samples were collected by intracerebral microdialysis with DL-nicotine as internal standard. Concentrations of nicotine and DL-nicotine in the sample were measured by HPLC-MS/MS. Main pharmacokinetic parameters were calculated and analyzed by Das 2.0 pharmacokinetic software. The recovery of nicotine and the delivery of DL-nicotine were the same. The fate of absorption and distribution was two compartment model and the values of t1/2alpha was 170.31 min, t1/2beta was 263.30 min and the AUC(0-infinity) was 2.75 x 10(5) microg x L(-1) min separately. DL-nicotine can be used to calibrate the recovery of nicotine, and the new method of stable isotope microdialysis can be used to study the pharmacokinetics of freely moving rat. It will make sense for the treatment of addiction of tobacco and provide a new thought for the research of pharmacokinetics-pharmacodynamic combination.