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Selected papers from the latest issue:
Evaluation of Enantioselective Binding of Propanocaine to Human Serum Albumin by Ultrafiltration and Electrokinetic Chromatography under intermediate precision conditions
05 February 2012, 21:52:56
Publication year: 2012
Source: Journal of Chromatography B, Available online 4 February 2012
María Amparo Martínez-Gómez, Laura Escuder-Gilabert, Rosa María Villanueva-Camañas, Salvador Sagrado, María José Medina-Hernández
Stereoselectivity in protein binding can have a significant effect on the pharmacokinetic and pharmacodynamic properties of chiral drugs. In this paper, the enantioselective binding of propanocaine (PRO) enantiomers to human serum albumin (HSA), the most relevant plasmatic protein in view of stereoselectivity, has been evaluated by incubation and ultrafiltration of racemic PRO-HSA mixtures and chiral analysis of the bound and unbound fractions by electrokinetic chromatography using HSA as chiral selector. Experimental conditions for the separation of PRO enantiomers using HSA as chiral selector and electrokinetic chromatography have been optimized. Affinity constants and protein binding in percentage (PB) were obtained for both enantiomers of PRO, as well as the enantioselectivity (ES) to HSA. Data were obtained in two independent working sessions (days). The influence of the session and fraction processed factors were examined. A univariate direct-estimation approach was used facilitating outliers’ identification and statistical comparison. Non-linear fitting of data was used to verify the stoichiometry and affinity estimations obtained by the direct approach. Robust statistics were applied to obtain reliable estimations of uncertainty, accounting for the factors (day and processed fraction), thus representing intermediate precision conditions. Mimickingin vivoexperimental conditions, information unapproachable byin vivoexperiments was obtained for PRO enantiomers interacting with HSA. For the first (E1) and the second (E2) eluted PRO enantiomers the results were: 1:1 stoichiometry, medium affinity constants, logKE1 = 3.20 ± 0.16 and logKE2 = 3.40 ± 0.14, medium protein binding percentage,PB = 48.7 and 60.1% for E1 and E2, respectively, and moderate but significant enantioselectivity,ES = KE2/KE1 = 1.5 ± 0.3.
Source: Journal of Chromatography B, Available online 4 February 2012
María Amparo Martínez-Gómez, Laura Escuder-Gilabert, Rosa María Villanueva-Camañas, Salvador Sagrado, María José Medina-Hernández
Stereoselectivity in protein binding can have a significant effect on the pharmacokinetic and pharmacodynamic properties of chiral drugs. In this paper, the enantioselective binding of propanocaine (PRO) enantiomers to human serum albumin (HSA), the most relevant plasmatic protein in view of stereoselectivity, has been evaluated by incubation and ultrafiltration of racemic PRO-HSA mixtures and chiral analysis of the bound and unbound fractions by electrokinetic chromatography using HSA as chiral selector. Experimental conditions for the separation of PRO enantiomers using HSA as chiral selector and electrokinetic chromatography have been optimized. Affinity constants and protein binding in percentage (PB) were obtained for both enantiomers of PRO, as well as the enantioselectivity (ES) to HSA. Data were obtained in two independent working sessions (days). The influence of the session and fraction processed factors were examined. A univariate direct-estimation approach was used facilitating outliers’ identification and statistical comparison. Non-linear fitting of data was used to verify the stoichiometry and affinity estimations obtained by the direct approach. Robust statistics were applied to obtain reliable estimations of uncertainty, accounting for the factors (day and processed fraction), thus representing intermediate precision conditions. Mimickingin vivoexperimental conditions, information unapproachable byin vivoexperiments was obtained for PRO enantiomers interacting with HSA. For the first (E1) and the second (E2) eluted PRO enantiomers the results were: 1:1 stoichiometry, medium affinity constants, logKE1 = 3.20 ± 0.16 and logKE2 = 3.40 ± 0.14, medium protein binding percentage,PB = 48.7 and 60.1% for E1 and E2, respectively, and moderate but significant enantioselectivity,ES = KE2/KE1 = 1.5 ± 0.3.
Highlights
► ► First evidence on enantioselective binding of propanocaine to human serum albumin ► Approximatein vivoconditions allowsin vitrodata unapproachable fromin vivoassays. ► Optimised experimental design reduces methodological errors ► Direct equations enable statistical advantages and robust results ► Data from two days and two processed fractions provide reliable uncertainty.Development and Validation of a Sensitive LC-MS/MS Assay for Simultaneous Quantitation of Ranolazine and Its Three Metabolites in Human Plasma
03 February 2012, 23:20:24
Publication year: 2012
Source: Journal of Chromatography B, Available online 3 February 2012
Yuan Wang, Xiaoyan Chen, Zuoming Sun, Yong Yang, Ying Zhang, ...
A rapid, sensitive and reliable LC-MS/MS method was developed and validated for the simultaneous determination of ranolazine and its three metabolites, CVT-2514, CVT-2738, and CVT-4786, in human plasma. The plasma samples were prepared by protein precipitation. Chromatographic separation was achieved on a Gemini C18column (50 mm × 2.0 mm, 5 μm) using methanol: 5 mM ammonium acetate as the mobile phase with gradient elution. Mass detection was carried out by electrospray ionization in both positive and negative ion multiple reaction monitoring (MRM) modes. The calibration curves were linear over a concentration range of 4 ng/mL to 2000 ng/mL for ranolazine, 4 ng/mL to 1000 ng/mL for CVT-2514 and CVT-2738 and 8 ng/mL to 1000 ng/mL for CVT-4786. The intra-day and inter-day accuracy and precision were within the acceptable limits of ±15% at all concentrations. The method was successfully applied for the simultaneous estimation of ranolazine and its three metabolites in human plasma from a clinical pharmacokinetics study.
Source: Journal of Chromatography B, Available online 3 February 2012
Yuan Wang, Xiaoyan Chen, Zuoming Sun, Yong Yang, Ying Zhang, ...
A rapid, sensitive and reliable LC-MS/MS method was developed and validated for the simultaneous determination of ranolazine and its three metabolites, CVT-2514, CVT-2738, and CVT-4786, in human plasma. The plasma samples were prepared by protein precipitation. Chromatographic separation was achieved on a Gemini C18column (50 mm × 2.0 mm, 5 μm) using methanol: 5 mM ammonium acetate as the mobile phase with gradient elution. Mass detection was carried out by electrospray ionization in both positive and negative ion multiple reaction monitoring (MRM) modes. The calibration curves were linear over a concentration range of 4 ng/mL to 2000 ng/mL for ranolazine, 4 ng/mL to 1000 ng/mL for CVT-2514 and CVT-2738 and 8 ng/mL to 1000 ng/mL for CVT-4786. The intra-day and inter-day accuracy and precision were within the acceptable limits of ±15% at all concentrations. The method was successfully applied for the simultaneous estimation of ranolazine and its three metabolites in human plasma from a clinical pharmacokinetics study.
Highlights
► A rapid and sensitive LC-MS/MS assay has been developed and validated. ► Ranolazine and three metabolites were simultaneously determined in human plasma. ► The LLOQ was 4 ng/mL for ranolazine, CVT-2514 and CVT-2738, and 8 ng/mL for CVT-4786. ► The method was applied to a pharmacokinetic study in humans.Determination of sinomenine sustained-release capsules in healthy Chinese volunteers by liquid chromatography tandem mass spectrometry
03 February 2012, 23:20:24
Publication year: 2012
Source: Journal of Chromatography B, Available online 2 February 2012
Meng-Xiang Su, Min Song, De-Zhu Sun, Hua Zhao, Xiao Gu, ...
A sensitive and selective liquid chromatographic tandem mass spectrometric method was developed and validated for the determination of sinomenine in human plasma. Plasma samples were precipitated using methanol with metronidazole as internal standard. Separation was carried out on an Inertsil ODS-3 column using a mixture of 0.2% ammonium acetate solution (A) and methanol (B) as the mobile phase with linear gradient elution as follows: 0 min (50%B) → 1.5 min (80%B) → 4.5 min (80%B) → 4.6 min (50%B) → 6.0 min (50%B). All mass data were obtained in the positive ion mode, and the fragmentation transitions for the selective multiple reaction monitoring werem/z330 →181 and 172 →128 for sinomenine and metronidazole, respectively. The method was fully validated to be accurate and precise with a linear range of 0.5–500 ng/mL and applied to a single- and multiple-dose pharmacokinetics study of sustained-release capsules of sinomenine hydrochloride in 20 healthy Chinese volunteers. After oral administration of a single 60-mg dose, theTmax,Cmax, AUC0–96andt1/2were 7.9 ± 2.0 h, 123 ± 22 ng/mL, 3032 ± 682 ng·h/mL and 13.4 ± 1.6 h, respectively. After oral administration of the 60 mg capsules twice-daily for 7 consecutive days, these parameters were 4.4 ± 3.6 h, 279 ± 69 ng/mL, 7333 ± 2096 ng·h/mL and 15.1 ± 1.3 h, respectively. The AUC andCmaxvalues after multiple-dose treatment were significantly higher than those after a single-dose treatment (P < 0.01), with an accumulation factor of 2.49 ± 0.77.
Source: Journal of Chromatography B, Available online 2 February 2012
Meng-Xiang Su, Min Song, De-Zhu Sun, Hua Zhao, Xiao Gu, ...
A sensitive and selective liquid chromatographic tandem mass spectrometric method was developed and validated for the determination of sinomenine in human plasma. Plasma samples were precipitated using methanol with metronidazole as internal standard. Separation was carried out on an Inertsil ODS-3 column using a mixture of 0.2% ammonium acetate solution (A) and methanol (B) as the mobile phase with linear gradient elution as follows: 0 min (50%B) → 1.5 min (80%B) → 4.5 min (80%B) → 4.6 min (50%B) → 6.0 min (50%B). All mass data were obtained in the positive ion mode, and the fragmentation transitions for the selective multiple reaction monitoring werem/z330 →181 and 172 →128 for sinomenine and metronidazole, respectively. The method was fully validated to be accurate and precise with a linear range of 0.5–500 ng/mL and applied to a single- and multiple-dose pharmacokinetics study of sustained-release capsules of sinomenine hydrochloride in 20 healthy Chinese volunteers. After oral administration of a single 60-mg dose, theTmax,Cmax, AUC0–96andt1/2were 7.9 ± 2.0 h, 123 ± 22 ng/mL, 3032 ± 682 ng·h/mL and 13.4 ± 1.6 h, respectively. After oral administration of the 60 mg capsules twice-daily for 7 consecutive days, these parameters were 4.4 ± 3.6 h, 279 ± 69 ng/mL, 7333 ± 2096 ng·h/mL and 15.1 ± 1.3 h, respectively. The AUC andCmaxvalues after multiple-dose treatment were significantly higher than those after a single-dose treatment (P < 0.01), with an accumulation factor of 2.49 ± 0.77.
Highlights
► LC–MS/MS quantification of sinomenon in human plasma was developed. ► This method achieved a LLOQ as low as 0.5 ng/ml with a simple pretreatment procedure. ► Clinical pharmacokinetic of sinomenine sustained-release capsules was characterized. ► The accumulation of sinomenine in body was observed after repeated dosing.A method for the simultaneous determination of mercapturic acids as biomarkers of exposure to 2-chloroprene and epichlorohydrin in human urine
03 February 2012, 23:20:24
Publication year: 2012
Source: Journal of Chromatography B, Available online 2 February 2012
Elisabeth Eckert, Gabriele Leng, Wolfgang Gries, Thomas Göen
We developed and validated an analytical method for the simultaneous determination of several chlorine and non-chlorine containing mercapturic acids in urine as specific metabolites of the hazardous chemicals 2-chloroprene and epichlorohydrin. The method involves an online column switching arrangement for online solid phase extraction of the analytes with subsequent analytical separation and detection using LC-MS/MS. The developed method enables for the first time the determination of Cl-MA-I (4-chloro-3-oxobutyl mercapturic acid), Cl-MA-II (4-chloro-3-hydroxybutyl mercapturic acid), Cl-MA-III (3-chloro-2-hydroxy-3-butenyl mercapturic acid) and HOBMA (4-hydroxy-3-oxobutyl mercapturic acid) as potential biomarkers of 2-chloroprene in urine. Additionally, CHPMA (3-chloro-2-hydroxypropyl mercapturic acid) as a specific metabolite of epichlorohydrin in urine and DHBMA (3,4-dihydroxybutyl mercapturic acid) can be determined. The analytical method proved to be both sensitive and reliable with detection limits ranging from 1.4 μg/L (for Cl-MA-III) to 4.2 μg/L (for HOBMA). Intra- and interday imprecision was determined to range from 4.7 to 11.8%. Due to the good accuracy and precision and the low limits of detection the developed method is well suited for application in biomonitoring studies in order to determine occupational exposure to 2-chloroprene and epichlorohydrin.
Source: Journal of Chromatography B, Available online 2 February 2012
Elisabeth Eckert, Gabriele Leng, Wolfgang Gries, Thomas Göen
We developed and validated an analytical method for the simultaneous determination of several chlorine and non-chlorine containing mercapturic acids in urine as specific metabolites of the hazardous chemicals 2-chloroprene and epichlorohydrin. The method involves an online column switching arrangement for online solid phase extraction of the analytes with subsequent analytical separation and detection using LC-MS/MS. The developed method enables for the first time the determination of Cl-MA-I (4-chloro-3-oxobutyl mercapturic acid), Cl-MA-II (4-chloro-3-hydroxybutyl mercapturic acid), Cl-MA-III (3-chloro-2-hydroxy-3-butenyl mercapturic acid) and HOBMA (4-hydroxy-3-oxobutyl mercapturic acid) as potential biomarkers of 2-chloroprene in urine. Additionally, CHPMA (3-chloro-2-hydroxypropyl mercapturic acid) as a specific metabolite of epichlorohydrin in urine and DHBMA (3,4-dihydroxybutyl mercapturic acid) can be determined. The analytical method proved to be both sensitive and reliable with detection limits ranging from 1.4 μg/L (for Cl-MA-III) to 4.2 μg/L (for HOBMA). Intra- and interday imprecision was determined to range from 4.7 to 11.8%. Due to the good accuracy and precision and the low limits of detection the developed method is well suited for application in biomonitoring studies in order to determine occupational exposure to 2-chloroprene and epichlorohydrin.
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