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Selected papers from the latest issue:
Pharmacokinetics and disposition study of calf thymus DNA in rats by applyingH-labelling method
20 February 2012, 22:51:34
Publication year: 2012
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 20 February 2012
Shuoye Yang, Qiuyang Zhang, Jiayin Chen, Deen Han, Di Zhao, ...
A tritium(H)-labelling method with high specificity was established to investigate the pharmacokinetics and disposition of the Calf thymus DNA(ctDNA) in rats. The plasma pharmacokinetics, tissue distribution, mass balance and excretion was characterized in SD rats, respectively. Rats were injected i.v. with radiolabeled ctDNA with the dose of 40 μCi/kg in each independent experiment.H-labeled ctDNA was eliminated rapidly in plasma, with the half-life estimated from 9-13 hours and preferentially accumulated in liver and lung, its concentration in all the tissues investigated decreased to very low level after 24 hours. ctDNA exhibited 80.8% accumulative recovery, excretion of radiolabel in urine and bile was nearly complete by 72 hours, which shown as the main excretion pathways, and the total recovery of excretion reached 77.9% within three days. In conclusion, ctDNA was rapidly eliminated in plasma and would not accumulate in tissues, parent ctDNA and its radioactive metabolites can be recovered almost completely in schedule time. All the results indicated that the in vitro use of ctDNA is safe and will not bring out potential risk.
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 20 February 2012
Shuoye Yang, Qiuyang Zhang, Jiayin Chen, Deen Han, Di Zhao, ...
A tritium(H)-labelling method with high specificity was established to investigate the pharmacokinetics and disposition of the Calf thymus DNA(ctDNA) in rats. The plasma pharmacokinetics, tissue distribution, mass balance and excretion was characterized in SD rats, respectively. Rats were injected i.v. with radiolabeled ctDNA with the dose of 40 μCi/kg in each independent experiment.H-labeled ctDNA was eliminated rapidly in plasma, with the half-life estimated from 9-13 hours and preferentially accumulated in liver and lung, its concentration in all the tissues investigated decreased to very low level after 24 hours. ctDNA exhibited 80.8% accumulative recovery, excretion of radiolabel in urine and bile was nearly complete by 72 hours, which shown as the main excretion pathways, and the total recovery of excretion reached 77.9% within three days. In conclusion, ctDNA was rapidly eliminated in plasma and would not accumulate in tissues, parent ctDNA and its radioactive metabolites can be recovered almost completely in schedule time. All the results indicated that the in vitro use of ctDNA is safe and will not bring out potential risk.
Highlights
► A tritium(H)-labelling method with high specificity was established; ► The pharmacokinetics and disposition of the ctDNA in rats were investigated in detail; ► Results showed that ctDNA was safe for therapeutic use.Risk analysis of analytical validations by probabilistic modification of FMEA
20 February 2012, 22:51:34
Publication year: 2012
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 20 February 2012
D.M. Barends, M.T. Oldenhof, M.J. Vredenbregt, M.J. Nauta
Risk analysis is a valuable addition to validation of an analytical chemistry process, enabling not only detecting technical risks, but also risks related to human failures. Failure Mode and Effect Analysis (FMEA) can be applied, using a categorical risk scoring of the occurrence, detection and severity of failure modes, and calculating the Risk Priority Number (RPN) to select failure modes for correction. We propose a probabilistic modification of FMEA, replacing the categorical scoring of occurrence and detection by their estimated relative frequency and maintaining the categorical scoring of severity. In an example, the results of traditional FMEA of a Near Infrared (NIR) analytical procedure used for the screening of suspected counterfeited tablets are re-interpretated by this probabilistic modification of FMEA. Using this probabilistic modification of FMEA, the frequency of occurrence of undetected failure mode(s) can be estimated quantatively, for each individual failure mode, for a set of failure modes, and the full analytical procedure.
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 20 February 2012
D.M. Barends, M.T. Oldenhof, M.J. Vredenbregt, M.J. Nauta
Risk analysis is a valuable addition to validation of an analytical chemistry process, enabling not only detecting technical risks, but also risks related to human failures. Failure Mode and Effect Analysis (FMEA) can be applied, using a categorical risk scoring of the occurrence, detection and severity of failure modes, and calculating the Risk Priority Number (RPN) to select failure modes for correction. We propose a probabilistic modification of FMEA, replacing the categorical scoring of occurrence and detection by their estimated relative frequency and maintaining the categorical scoring of severity. In an example, the results of traditional FMEA of a Near Infrared (NIR) analytical procedure used for the screening of suspected counterfeited tablets are re-interpretated by this probabilistic modification of FMEA. Using this probabilistic modification of FMEA, the frequency of occurrence of undetected failure mode(s) can be estimated quantatively, for each individual failure mode, for a set of failure modes, and the full analytical procedure.
Highlights
► FMEA is a valuable addition to analytical validation ► Traditional FMEA is modified by replacing categorical scores by probabilities ► Probabilistic modification of FMEA has added values ► Frequencies of occurence of undetected failure modes are now quantifiedEditorial Board
19 February 2012, 00:52:41
Publication year: 2012
Source: Journal of Pharmaceutical and Biomedical Analysis, Volume 62, 25 March 2012, Pages CO2
[No author name available]
Source: Journal of Pharmaceutical and Biomedical Analysis, Volume 62, 25 March 2012, Pages CO2
[No author name available]
Acetylcholinesterase capillary enzyme reactor for screening and characterization of selective inhibitors
19 February 2012, 00:52:41
Publication year: 2012
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 18 February 2012
Joyce Izidoro da Silva, Marcela Cristina de Moraes, Lucas Campos Cursino Vieira, Arlene Gonçalves Corrêa, Quezia Bezerra Cass, ...
The aim of the present work is to report on the optimized preparation of capillary enzyme reactors (ICERs) based on acetylcholinesterase (AChE, E. C. 3.1.1.7), for the screening of selective inhibitors. The AChE-ICERs were prepared by using the homobifunctional linker glutaraldehyde through Schiff base linkage. The enzyme was anchored onto a modified fused silica capillary and employed as an LC biochromatogaphy column for online studies, with UV-Vis detection. Not only did the tailored AChE-ICER result in maintenance of the activity of the immobilized enzyme, but it also significantly improved the stability of the enzyme in the presence of organic solvents. In addition, the kinetic studies demonstrated that the enzyme retained its activity with high stability, preserving its initial activity over 10 months. The absence of non-specific matrix interactions, immediate recovery of the enzymatic activity, and short analysis time were the main advantages of this AChE-ICER. The use of AChE-ICER in the ligands recognition assay was validated by evaluation of four known reversible inhibitors (galanthamine, tacrine, propidium, and rivastigmine), and the same order of inhibitory potencies described in the literature was found. The immobilized enzyme was utilized in the screening of 21 coumarin derivatives. In this library, two new potent inhibitors were identified: coumarins20(IC5017.14 ± 3.50 μM) and21(IC506.35 ± 1.20 μM), which were compared to the standard galanthamine (IC5012.68 ± 2.40 μM). Considering the high inhibitory activities of these compouds, with respect to the AChE-ICER, the mechanism of action was investigated. Both coumarins20and21exhibited a competitive mechanism of action, furnishing Kivalues of 8.04 ± 0.18 and 2.67 ± 0.18 μM, respectively. The results revealed that the AChE-ICER developed herein represents a useful tool for the biological screening of inhibitor candidates and evaluation of action mechanism.
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 18 February 2012
Joyce Izidoro da Silva, Marcela Cristina de Moraes, Lucas Campos Cursino Vieira, Arlene Gonçalves Corrêa, Quezia Bezerra Cass, ...
The aim of the present work is to report on the optimized preparation of capillary enzyme reactors (ICERs) based on acetylcholinesterase (AChE, E. C. 3.1.1.7), for the screening of selective inhibitors. The AChE-ICERs were prepared by using the homobifunctional linker glutaraldehyde through Schiff base linkage. The enzyme was anchored onto a modified fused silica capillary and employed as an LC biochromatogaphy column for online studies, with UV-Vis detection. Not only did the tailored AChE-ICER result in maintenance of the activity of the immobilized enzyme, but it also significantly improved the stability of the enzyme in the presence of organic solvents. In addition, the kinetic studies demonstrated that the enzyme retained its activity with high stability, preserving its initial activity over 10 months. The absence of non-specific matrix interactions, immediate recovery of the enzymatic activity, and short analysis time were the main advantages of this AChE-ICER. The use of AChE-ICER in the ligands recognition assay was validated by evaluation of four known reversible inhibitors (galanthamine, tacrine, propidium, and rivastigmine), and the same order of inhibitory potencies described in the literature was found. The immobilized enzyme was utilized in the screening of 21 coumarin derivatives. In this library, two new potent inhibitors were identified: coumarins20(IC5017.14 ± 3.50 μM) and21(IC506.35 ± 1.20 μM), which were compared to the standard galanthamine (IC5012.68 ± 2.40 μM). Considering the high inhibitory activities of these compouds, with respect to the AChE-ICER, the mechanism of action was investigated. Both coumarins20and21exhibited a competitive mechanism of action, furnishing Kivalues of 8.04 ± 0.18 and 2.67 ± 0.18 μM, respectively. The results revealed that the AChE-ICER developed herein represents a useful tool for the biological screening of inhibitor candidates and evaluation of action mechanism.
Graphical abstract
Highlights
► Acetylcholinesterase from Electric eel was immobilized onto a fused silica capillary resulting AChE-ICER. ► AChE-ICER was employed as an LC biochromatography column in on line inhibitor studies. ► Selected compounds20(IC50= 17.14 ± 3.50 μM and Ki= 8.04 ± 0.18) and21(IC50= 6.35 ± 1.20 μM and Ki= 2.67 ± 0.18 μM). ► Standard galanthamine (IC50= 12.68 ± 2.40 μM and Ki= 10.90 ± 0.51 μM). ► The obtanid data suggest the applicability of the method developed herein for the identification of new ligands.Simultaneous determination of antidementia drugs in human plasma: Procedure transfer from HPLC-MS to UPLC-MS/MS
19 February 2012, 00:52:41
Publication year: 2012
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 18 February 2012
Muriel Noetzli, Nicolas Ansermot, Maria Dobrinas, Chin B. Eap
A previously developed high performance liquid chromatography mass spectrometry (HPLC-MS) procedure for the simultaneous determination of antidementia drugs, including donepezil, galantamine, memantine, rivastigmine and its metabolite NAP 226-90, was transferred to an ultra performance liquid chromatography system coupled to a tandem mass spectrometer (UPLC-MS/MS). The drugs and their internal standards ([H7]-donepezil, [C,H3]-galantamine, [C2,H6]-memantine, [H6]-rivastigmine) were extracted from 250 μL human plasma by protein precipitation with acetonitrile. Chromatographic separation was achieved on a reverse phase column (BEH C18 2.1 × 50 mm; 1.7 μm) with a gradient elution of an ammonium acetate buffer at pH 9.3 and acetonitrile at a flow rate of 0.4 mL/min and an overall run time of 4.5 min. The analytes were detected on a tandem quadrupole mass spectrometer operated in positive electrospray ionization mode, and quantification was performed using multiple reaction monitoring. The method was validated according to the recommendations of international guidelines over a calibration range of 1-300 ng/mL for donepezil, galantamine and memantine, and 0.2-50 ng/mL for rivastimgine and NAP 226-90. The trueness (86-108%), repeatability (0.8-8.3%), intermediate precision (2.3-10.9%) and selectivity of the method were found to be satisfactory. Matrix effects variability was inferior to 15% for the analytes and inferior to 5% after correction by internal standards. A method comparison was performed with patients’ samples showing similar results between the HPLC-MS and UPLC-MS/MS procedures. Thus, this validated UPLC-MS/MS method allows to reduce the required amount of plasma, to use a simplified sample preparation, and to obtain a higher sensitivity and specificity with a much shortened run-time.
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 18 February 2012
Muriel Noetzli, Nicolas Ansermot, Maria Dobrinas, Chin B. Eap
A previously developed high performance liquid chromatography mass spectrometry (HPLC-MS) procedure for the simultaneous determination of antidementia drugs, including donepezil, galantamine, memantine, rivastigmine and its metabolite NAP 226-90, was transferred to an ultra performance liquid chromatography system coupled to a tandem mass spectrometer (UPLC-MS/MS). The drugs and their internal standards ([H7]-donepezil, [C,H3]-galantamine, [C2,H6]-memantine, [H6]-rivastigmine) were extracted from 250 μL human plasma by protein precipitation with acetonitrile. Chromatographic separation was achieved on a reverse phase column (BEH C18 2.1 × 50 mm; 1.7 μm) with a gradient elution of an ammonium acetate buffer at pH 9.3 and acetonitrile at a flow rate of 0.4 mL/min and an overall run time of 4.5 min. The analytes were detected on a tandem quadrupole mass spectrometer operated in positive electrospray ionization mode, and quantification was performed using multiple reaction monitoring. The method was validated according to the recommendations of international guidelines over a calibration range of 1-300 ng/mL for donepezil, galantamine and memantine, and 0.2-50 ng/mL for rivastimgine and NAP 226-90. The trueness (86-108%), repeatability (0.8-8.3%), intermediate precision (2.3-10.9%) and selectivity of the method were found to be satisfactory. Matrix effects variability was inferior to 15% for the analytes and inferior to 5% after correction by internal standards. A method comparison was performed with patients’ samples showing similar results between the HPLC-MS and UPLC-MS/MS procedures. Thus, this validated UPLC-MS/MS method allows to reduce the required amount of plasma, to use a simplified sample preparation, and to obtain a higher sensitivity and specificity with a much shortened run-time.
Highlights
► Four antidementia drugs were simultaneously quantified by UPLC-MS/MS ► A procedure transfer from HPLC-MS to UPLC-MS/MS was carried out ► The new UPLC procedure is faster, more sensitive and more specific ► Validation showed good results concerning accuracy, precision and matrix effects ► A Passing-Bablok analysis was performed to compare the HPLC and UPLC proceduresTentative identification of phase I metabolites of HU-210, a classical synthetic cannabinoid, by LC-MS/MS
19 February 2012, 00:52:41
Publication year: 2012
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 18 February 2012
Unyong Kim, Ming Ji Jin, Jaeick Lee, Sang Beom Han, Moon Kyo In, ...
(6aR, 10aR)-9-(Hydroxymethyl)-6, 6-dimethyl-3-(2-methyloctan-2-yl)-6a, 7, 10, 10a-tetrahydrobenzo [c]chromen-1-ol (HU-210) is a synthetic cannabinoid, with a classical cannabinoid structure similar to Δ-tetrahydrocannabinol (Δ-THC). In this study, thein vitrometabolism of HU-210 was investigated in human liver microsomes to characterize associated phase I metabolites. HU-210 was incubated with human liver microsomes, and the reaction mixture was analyzed using LC-MS/MS. HU-210 was metabolized in human liver microsomes, yielding about 24 metabolites. These metabolites were structurally characterized on the basis of accurate mass analyses and MS/MS fragmentation patterns. The major metabolic route for HU-210 was oxygenation. Metabolites M1–M7 were identified as mono-oxygenated metabolites; M8–M15, mono-hydroxylated metabolites; M16–M20, di-oxygenated metabolites; and M21–M24, di-hydroxylated metabolites. These results provide evidence forin vivoHU-210 metabolism, and they may be applied to the analysis of HU-210 and its relevant metabolites in biological samples.
Source: Journal of Pharmaceutical and Biomedical Analysis, Available online 18 February 2012
Unyong Kim, Ming Ji Jin, Jaeick Lee, Sang Beom Han, Moon Kyo In, ...
(6aR, 10aR)-9-(Hydroxymethyl)-6, 6-dimethyl-3-(2-methyloctan-2-yl)-6a, 7, 10, 10a-tetrahydrobenzo [c]chromen-1-ol (HU-210) is a synthetic cannabinoid, with a classical cannabinoid structure similar to Δ-tetrahydrocannabinol (Δ-THC). In this study, thein vitrometabolism of HU-210 was investigated in human liver microsomes to characterize associated phase I metabolites. HU-210 was incubated with human liver microsomes, and the reaction mixture was analyzed using LC-MS/MS. HU-210 was metabolized in human liver microsomes, yielding about 24 metabolites. These metabolites were structurally characterized on the basis of accurate mass analyses and MS/MS fragmentation patterns. The major metabolic route for HU-210 was oxygenation. Metabolites M1–M7 were identified as mono-oxygenated metabolites; M8–M15, mono-hydroxylated metabolites; M16–M20, di-oxygenated metabolites; and M21–M24, di-hydroxylated metabolites. These results provide evidence forin vivoHU-210 metabolism, and they may be applied to the analysis of HU-210 and its relevant metabolites in biological samples.
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