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Individual variation in pharmacokinetics of faropenem is significant. We attempted to predict drug response of faropenem using a pharmacometabonomic approach. Metabolic profiling was performed on predose plasma samples from 36 healthy volunteers by gas chromatography-mass spectrometry (GC/MS), with 204 endogenous metabolites detected. Plasma concentration was measured after drug administration, using high pressure liquid chromatography-tandem mass spectroscopy (LC/MS/MS), and the pharmacokinetic parameters were calculated. Then a two-stage partial least squares strategy was employed to screen potential biomarkers and predict the pharmacokinetic parameters of faropenem. The results showed a good prediction of AUC and C max with the screened biomarkers, and metabolites such as valine, proline, aspartic acid, gluconic acid, glucuronic acid, and 2-ketoisocaproic acid were indicated as candidate biomarkers. Finally, we explored the mechanism of individual variation by pathway enrichment analysis, and it suggested that organic anion transporter 1 (OAT1) and 3 (OAT3) might be responsible for individual variation of faropenem, and this hypothesis was verified by an experiment in rats.

A simple, rapid and highly sensitive LC-MS/MS method was developed and validated for the determination of ketoconazole in human plasma. Sample preparation was accomplished through a single step liquid-liquid extraction by ethyl acetate. The chromatography separation was carried out on a Hedera CN (150mm×2.1mm, 5μm) column with isocratic elution using acetonitrile and 10mM ammonium acetate containing 0.1% formic acid (45:55, v/v) as the mobile phase. The flow rate was 0.5mL/min. Detection was performed in the positive ion electrospray ionization mode using multiple reaction monitoring of the transitions of 531.2→489.3 and 286.1→217.1 for ketoconazole and letrozole (the internal standard), respectively. The method exhibited good linearity over the concentration range of 0.01-12ng/mL for ketoconazole. The intra- and inter-batch precision and accuracy of ketoconazole were all within the acceptable criteria. The method was successfully applied to a clinical study of the exposure to ketoconazole in Chinese seborrheic dermatitis patients after topical administration of two ketoconazole formulations of foam and lotion, respectively. The study results showed that there was little systemic absorption of ketoconazole in patients for the two formulations, and the ketoconazole foam and lotion are safe therapeutic drugs for seborrheic dermatitis patients., (Copyright © 2016. Published by Elsevier B.V.)

Corynoline and acetycorynoline, the major active components derived from Corydalis bungeana Herba, showed multiple pharmacological activities. However, quantification of the two compounds in human urine has not been reported. A simple liquid chromatography with tandem mass spectrometry method for the simultaneous determination of corynoline and acetycorynoline in human urine has been developed and fully validated. The analytes were extracted from urine samples by simple liquid-liquid extraction. Chromatographic separation was achieved on a Hedera ODS-2C18 column with the mobile phase of water (containing 0.5% formic acid) and acetonitrile (28:72, v/v) at a flow rate of 0.4mL/min. A tandem mass spectrometric detection was conducted using multiple reaction monitoring via an electrospray ionization source in positive mode. The monitored ion transitions were m/z 368.1→289.1 for corynoline, m/z 410.2→289.2 for acetycorynoline and m/z 380.2→243.2 for donepezil (internal standard), respectively. The calibration curves were linear (correlation coefficients>0.9970) over the concentration ranges of 3.0-3000pg/mL for corynoline and 3.0-1000pg/mL for acetycorynoline. The established method was highly sensitive with the lower limit of quantification (LLOQ) of 3.0pg/mL for both analytes. The intra- and inter-day precision was lower than 10% in terms of relative standard deviation for the low, medium, and high quality control samples, and lower than 16% for the LLOQ samples of the analytes. The accuracy was within ±10% in terms of relative error for both analytes. The method was successfully applied to a urinary excretion study after oral administration of the Chinese medicine formula Shuanghua Baihe tablets in healthy volunteers. The urinary excretion profiles of corynoline and acetycorynoline in human were first reported. The results of this study suggest that renal excretion was not the main excretion pathway of corynoline and acetycorynoline in humans., (Copyright © 2016 Elsevier B.V. All rights reserved.)

An LC-MS/MS method was developed and validated for the simultaneous determination of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine in human urine. The sample preparation procedure involved the four-fold dilution of the urine samples with acetonitrile/water (1:3, v/v). The chromatographic separation was achieved on a Hedera ODS-2 column under gradient elution at a flow rate of 0.4 mL/min with acetonitrile and water containing 0.5% formic acid as the mobile phase. The mass detection was performed in the positive mode. Calibration curves of the seven alkaloids showed good linearity (correlation coefficients>0.9973) over their concentration ranges. To meet the requirements of urinary excretion study for each alkaloid in human, the lower limit of quantification was set at different values from 0.05063 ng/mL to 2.034 ng/mL for the seven alkaloids, respectively. The intra- and inter-batch precision and accuracy were all within ± 15%. No matrix effect was observed for the analytes. The validated method was applied to the excretion study for the seven alkaloids in healthy Chinese volunteers after oral administration of Shuanghua Baihe tablets. The average 72 h cumulative urinary excretion of magnoflorine, berberrubine, jatrorrhizine, coptisine, epiberberine, palmatine and berberine accounted for 1.81%, 0.27%, 0.29%, 0.046%, 0.027%, 0.010% and 0.021% of the respective administered dose., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Shuanghua Baihe tablets (SBT) is a traditional Chinese medicinal formula which has been used to treat recurrent aphthous stomatitis for many years. To study the pharmacokinetic profiles of berberine, epiberberine, coptisine, palmatine, jatrorrhizine, magnoflorine, berberrubine, corynoline and acetylcorynoline in human after administration of SBT, a sensitive liquid chromatography-tandem mass spectrometry method was developed and fully validated for the simultaneous quantification of these nine alkaloids in human plasma. After protein precipitation, the nine alkaloids in human plasma sample was separated on a Hanbon C18 (150mm×2.1mm, 5μm) column with gradient elution using methanol and 0.5% formic acid water solution, and detected by a triple quadrupole mass spectrometer with an electrospray ionization source. It is a challenge to design different calibration ranges for different analytes in a bioanalytical method for simultaneous determination of multi-analytes in bio-samples. To ensure that each alkaloid in the plasma was determined accurately by the simultaneous quantitation method, the upper limits of quantification for the nine alkaloids were designed at 100, 300, 800, 1800 and 5000pg/mL, respectively, according to the maximum plasma concentration value of each alkaloid obtained from the pilot pharmacokinetic study. The lower limit of quantification was 15pg/mL for berberine, epiberberine, coptisine, magnoflorine, berberrubine, corynoline and acetylcorynoline, while for palmatine and jatrorrhizine it was 1.5pg/mL. This method was successfully applied to investigate the pharmacokinetic profiles of the nine alkaloids in healthy Chinese volunteers after a single oral administration of SBT., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A highly sensitive and rapid ultra high performance liquid chromatography with tandem mass spectrometry method has been developed and validated for the determination of glucosamine in human plasma using miglitol as the internal standard. Special attention was paid to achieve the high throughput and sensitivity of the established method, and the absence of a matrix effect on the analytes. The sample preparation procedure involved a simple deproteinization step. The chromatographic separation was achieved on a Waters ACQUITY HSS Cyano column using a mixture of acetonitrile/2 mM ammonium acetate solution containing 0.03% formic acid (80:20, v/v) as the mobile phase with a very short run time of 1.5 min. This method was validated over the concentration range of 10-3000 ng/mL for glucosamine. The intra- and inter-batch precision was <13.9% for the low, medium, and high quality control samples. The established method is highly sensitive with a lower limit of quantification of 10 ng/mL, low enough to determine the circadian rhythm on endogenous glucosamine level in human plasma, which has not been reported in detail until now. The method was successfully applied to characterize the pharmacokinetic profile of glucosamine in healthy volunteers following a single oral administration of 750 or 1500 mg glucosamine hydrochloride., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A simple, selective and sensitive LC-MS-MS method has been developed and validated to simultaneously quantify zofenopril and its active metabolite zofenoprilat in human plasma, using diazepam as internal standard. 1,4-Dithiothreitol was used as a reducer to release and stabilize the thiol group of zofenoprilat from dimer and mixed forms with endogenous thiols in the treatment of plasma samples. After a liquid-liquid extraction with methyl tert-butyl ether under acidic conditions, the post-treatment samples were analyzed on an Agilent ZORBAX Eclipse XDB-C8 column interfaced with a triple-quadruple tandem mass spectrometer using positive electrospray ionization. A solution of methanol and 0.1% formic acid solution (85 : 15, v/v) was used as the isocratic mobile phase with a flow rate of 0.2 mL/min. The method was validated to demonstrate the specificity, lower limit of quantitation, accuracy and precision of measurements. The validated LC-MS-MS method has been successfully applied to study the pharmacokinetics of zofenopril calcium in healthy Chinese volunteers., (© Crown copyright 2014.)

To study the systemic exposure of tazarotene formulation after topical administration, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous determination of tazarotene and tazarotenic acid in minipig plasma. Similar extraction recoveries for both analytes were obtained after the plasma samples were acidified by glacial acetic acid (5%) and extracted by ethyl ether-cyclohexane (4:1, v/v). Separation of the analytes was achieved within a short time by the addition of 0.1% formic acid to the mobile phase. Gradient elution was used to avoid the matrix effect. The method was linear over the concentration range of 10-600 pg/mL for both analytes. The data of intra- and inter-run precision and accuracy were lower than 5.2%, 7.3% and 7.3% for both analytes. The developed method can be applied to investigate the transdermal pharmacokinetics and the systemic exposure of tazarotene formulation after topical administration., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Fast and sensitive liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (LC-APCI-MS) method for the specific determination of viaminate in 14 kinds of rat tissues pre-treated with simple procedure was developed and validated. Biological samples were prepared by direct precipitation to skin, stomach, intestine, and liver and extracted by liquid-liquid extraction to lung, kidney, muscle, spleen, brain, fat, testes (male and female), eye, and heart. After addition of menaquinon as internal standard to tissue homogenate, the supernatant was injected into the isocratic chromatographic system using a Waters Symmetry C8 column and methanol-water-formic acid (93:7:0.1) as the eluent. The eluate was completely led into an APCI interface with selected ion monitoring mode and the analytes were quantified using triple quadrupole MS. The assays were successfully validated in the ranges 0.02-20 ng/mL for lung, 0.02-10 ng/mL for kidney, spleen, muscle, brain, fat, eye, and heart, 0.05-10 ng/mL for testicle, 0.4-100 ng/mL for liver, skin and intestine, and 1.0-200 ng/mL for stomach. The accurate and precise studies showed good reproducibility with coefficients of variation below 8.5% and the recoveries range from 90 to 109%. The analytes were chemically stable under all relevant conditions and the assays were applied in tissue distribution study. The results showed that the viaminate concentration was high in skin, low in kidney, and almost undetectable in eye and brain.

A new method for simultaneous determination of amiloride and hydrochlorothiazide by liquid chromatography/electrospray tandem mass spectrometry (LC/MS/MS) operated in positive and negative ionization switching mode was developed and validated. Protein precipitation with acetonitrile was selected for sample preparation. The analytes were separated on a Phenomenex Curosil-PFP (250x4.6 mm, 5 microm) column by a gradient elution with a mobile phase consisting of 0.15% formic acid solution containing 0.23% ammonium acetate and methanol pumped at a flow rate of 1.0 mL.min(-1). Rizatriptan was used as the internal standard (IS) for quantification. The determination was carried out on a Waters Quattro-micro triple-quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode using the following transitions monitored simultaneously: positive m/z 230-->171 for amiloride, m/z 270-->158 for rizatriptan, and negative m/z 296-->205 for hydrochlorothiazide. The lower limits of quantification (LLOQs) were 0.1 and 1.0 ng.mL(-1) for amiloride and hydrochlorothiazide, respectively, which were lower than other published methods by using ultraviolet (UV), fluorimetric or mass spectrometric detection. The intra- and inter-day precision and accuracy were studied at three different concentration levels and were always better than 15% (n=5). This simple and robust LC/MS/MS method was successfully applied to the pharmacokinetic study of compound amiloride and hydrochlorothiazide tablets in healthy male Chinese volunteers., (Copyright (c) 2007 John Wiley & Sons, Ltd.)