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An ultra-sensitive liquid chromatography tandem mass spectrometry method for the simultaneous quantification of 2H6-alectinib and alectinib in human plasma to support a microtracer food-effect trial
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-28 DOI: 10.1016/j.jchromb.2025.124488
L.T. van der Heijden , M.M. Tibben , M.I. Mohmaed Ali , L.G.J. Aardenburg , N. Steeghs , J.H. Beijnen , H. Rosing , A.D.R. Huitema
A liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of 2H6-alectinib and alectinib was developed and validated for the support of a pilot microtracer food-effect trial. The aim of the bioanalytical method was the simultaneous quantification of low 2H6-alectinib concentrations and high alectinib concentrations that are present in study samples, using a single sample pre-treatment and analysis method. Sample preparation consisted of liquid-liquid extraction with tert-butyl methyl ether (TBME). The final extract was injected on a C18 column (1.7 μm particles, 50 × 2.1 mm ID) with gradient elution. A triple quadruple mass spectrometer operating in positive method was used for detection and quantification. The validated concentration ranges were from 5 to 400 pg/mL for 2H6-alectinib and from 25 to 2000 ng/mL for alectinib. The bias was within ±3.5 % and ± 5.1 % and precisions ≤5.7 % and ≤ 1.9 % for 2H6-alectinib and alectinib, respectively. By correcting for the interference of natural abundant isotopes of alectinib, 2H6-alectinib plasma concentrations between 1 and 5 pg/mL could be quantified, with bias was within ±15.9 % and precision ≤12.5 % in the presence of 400 ng/mL or 800 ng/mL alectinib. The clinical application was successfully applied to quantify 2H6-alectinib and alectinib in plasma samples from a participant enrolled in a microtracer food-effect study.
{"title":"An ultra-sensitive liquid chromatography tandem mass spectrometry method for the simultaneous quantification of 2H6-alectinib and alectinib in human plasma to support a microtracer food-effect trial","authors":"L.T. van der Heijden ,&nbsp;M.M. Tibben ,&nbsp;M.I. Mohmaed Ali ,&nbsp;L.G.J. Aardenburg ,&nbsp;N. Steeghs ,&nbsp;J.H. Beijnen ,&nbsp;H. Rosing ,&nbsp;A.D.R. Huitema","doi":"10.1016/j.jchromb.2025.124488","DOIUrl":"10.1016/j.jchromb.2025.124488","url":null,"abstract":"<div><div>A liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of <sup>2</sup>H<sub>6</sub>-alectinib and alectinib was developed and validated for the support of a pilot microtracer food-effect trial. The aim of the bioanalytical method was the simultaneous quantification of low <sup>2</sup>H<sub>6</sub>-alectinib concentrations and high alectinib concentrations that are present in study samples, using a single sample pre-treatment and analysis method. Sample preparation consisted of liquid-liquid extraction with tert-butyl methyl ether (TBME). The final extract was injected on a C18 column (1.7 μm particles, 50 × 2.1 mm ID) with gradient elution. A triple quadruple mass spectrometer operating in positive method was used for detection and quantification. The validated concentration ranges were from 5 to 400 pg/mL for <sup>2</sup>H<sub>6</sub>-alectinib and from 25 to 2000 ng/mL for alectinib. The bias was within ±3.5 % and ± 5.1 % and precisions ≤5.7 % and ≤ 1.9 % for <sup>2</sup>H<sub>6</sub>-alectinib and alectinib, respectively. By correcting for the interference of natural abundant isotopes of alectinib, <sup>2</sup>H<sub>6</sub>-alectinib plasma concentrations between 1 and 5 pg/mL could be quantified, with bias was within ±15.9 % and precision ≤12.5 % in the presence of 400 ng/mL or 800 ng/mL alectinib. The clinical application was successfully applied to quantify <sup>2</sup>H<sub>6</sub>-alectinib and alectinib in plasma samples from a participant enrolled in a microtracer food-effect study.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124488"},"PeriodicalIF":2.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143168929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Detection and application of 40 piperazine compounds in hair suitable for rapid separation of isomers 检测和应用头发中的 40 种哌嗪化合物,以快速分离异构体。
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-28 DOI: 10.1016/j.jchromb.2025.124473
Jinting Liu , Xin Wang , Wanting Xie , Liying Zhou , Lina Pei , Shuo Yang , Guoqing Gao , Keming Yun , Yan Shi
A simple and sensitive procedure, using benzylpiperazine-D7 (BZP-D7) as an internal standard, has been developed and validated for the qualitative and quantitative analysis of 40 piperazines in hair. Drugs were extracted from 20 mg of hair with 0.5 mL of methanol containing 1 ng/mL BZP-D7. After ultrasonication, centrifugation and filtration, the supernatant was analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) operating in the multiple reaction monitoring mode. Piperazine-type substances were separated in 10 min on a T3 column using a mobile phase gradient composed of A (water, formic acid 0.1 %, acetonitrile 5 %, and 20 mmol/L ammonium acetate) and B (acetonitrile). The developed and validated method showed good selectivity, sensitivity (limit of detection: 0.5–20 pg/mg and lower limit of quantitation: 5–20 pg/mg), linearity (R2 > 0.99), accuracy, precision, and dilution integrity. The method also showed good recovery and acceptable matrix effects for most of the targeted compounds. This analytical approach was successfully applied for the identification and quantification of piperazine-type substances in hair from rat and guinea pig.
{"title":"Detection and application of 40 piperazine compounds in hair suitable for rapid separation of isomers","authors":"Jinting Liu ,&nbsp;Xin Wang ,&nbsp;Wanting Xie ,&nbsp;Liying Zhou ,&nbsp;Lina Pei ,&nbsp;Shuo Yang ,&nbsp;Guoqing Gao ,&nbsp;Keming Yun ,&nbsp;Yan Shi","doi":"10.1016/j.jchromb.2025.124473","DOIUrl":"10.1016/j.jchromb.2025.124473","url":null,"abstract":"<div><div>A simple and sensitive procedure, using benzylpiperazine-D<sub>7</sub> (BZP-D<sub>7</sub>) as an internal standard, has been developed and validated for the qualitative and quantitative analysis of 40 piperazines in hair. Drugs were extracted from 20 mg of hair with 0.5 mL of methanol containing 1 ng/mL BZP-D<sub>7</sub>. After ultrasonication, centrifugation and filtration, the supernatant was analyzed by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC–MS/MS) operating in the multiple reaction monitoring mode. Piperazine-type substances were separated in 10 min on a T<sub>3</sub> column using a mobile phase gradient composed of A (water, formic acid 0.1 %, acetonitrile 5 %, and 20 mmol/L ammonium acetate) and B (acetonitrile). The developed and validated method showed good selectivity, sensitivity (limit of detection: 0.5–20 pg/mg and lower limit of quantitation: 5–20 pg/mg), linearity (R<sup>2</sup> &gt; 0.99), accuracy, precision, and dilution integrity. The method also showed good recovery and acceptable matrix effects for most of the targeted compounds. This analytical approach was successfully applied for the identification and quantification of piperazine-type substances in hair from rat and guinea pig.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124473"},"PeriodicalIF":2.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073093","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Interpretation of negative-ion chemical ionization GC–MS and GC–MS/MS mass spectra of perfluorinated organic analyte derivatives: Consideration of reduction reactions in the gas phase
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-28 DOI: 10.1016/j.jchromb.2025.124487
Dimitrios Tsikas
<div><div>The main priniciples of gas chromatography–mass spectrometry (GC–MS) and gas chromatography-tandem mass spectrometry (GC–MS/MS) are: 1) separation of mostly derivatized analytes in the lumen of temperature-programmed gas chromatography (GC) fused-silica capillary columns, 2) ionization of gaseous charge-free analyte derivatives in the ion-source by means of electrons (electron ionization, EI) or in combination with a reagent gas such as methane (chemical ionization, CI), and 3) separation of simply ionized analytes or fragments in electric and/or magnetic fields due to their mass-to-charge ratio (<em>m/z</em>). EI generates (radical) cations, whereas CI is used to analyze either simply positively (positive-ion chemical ionization, PICI) or simply negatively charged analytes (negative-ion chemical ionization, NICI). In general, NICI in combination with the use of fluorinated (F) derivatization reagents is used in quantitative analyses as fluorinated analytes are softly ionized thus producing anions in high abundance and of high intensity. In quantitative analyses by GC-NICI-MS and GC-NICI-MS/MS, the position of the negative charge in the detected anions is secondary and in many cases unknown. The question of the position of the negative charge in analyte anions formed by NICI in GC-MS and GC-MS/MS is basically of theoretical interest and poorly addresed. The present article discusses this issue in detail. Previously reported GC-NICI-MS and GC-NICI-MS/MS quantitative methods for different classes of analytes, such as amino acids, fatty acids and drugs alongside their <sup>2</sup>H-, <sup>13</sup>C-, <sup>15</sup>N- and <sup>18</sup>O-isotopologs, after derivatization with fluorinated reagents including pentafluorobenzyl bromide (PFB-Br), pentafluorobenzoyl chloride (PFB-COCl) and pentafluoropropionic anhydride (PFPA) serve as examples and resources of data. ChemDraw Professional software was used to construct chemical structures of analytes and ions found in GC-NICI-MS and GC-NICI-MS/MS mass spectra. The results of the present study provide unique insights into the gas-phase reactions that take place in the ion-source of GC-MS and in the collision-chamber of GC-MS/MS instruments mainly based on the quadrupole (Q) technology. Paradoxically, the negative charge cannot be always assigned in precursor and product ions by standard rules of chemistry, unlike in EI and PICI. For example, PFB esters of fatty acids and eicosanoids (R-COO-PFB) ionize to form their carboxylates with the negative charge being definetly located in the carboxylic groups (R-COO<sup>−</sup>, [M-PFB]<sup>−</sup>). In contrast, methyl ester pentafluoropropionyl derivatives of amino acids ionize readily and abundantly under NICI conditions, yet the negative charge cannot be always asigned with apodictic certainty, even not for the calibrating/tuning compound perfluorotributylamine (PFTBA). The <em>paradox</em> vanishes when considering gas-phase reactions in the ion-source
{"title":"Interpretation of negative-ion chemical ionization GC–MS and GC–MS/MS mass spectra of perfluorinated organic analyte derivatives: Consideration of reduction reactions in the gas phase","authors":"Dimitrios Tsikas","doi":"10.1016/j.jchromb.2025.124487","DOIUrl":"10.1016/j.jchromb.2025.124487","url":null,"abstract":"&lt;div&gt;&lt;div&gt;The main priniciples of gas chromatography–mass spectrometry (GC–MS) and gas chromatography-tandem mass spectrometry (GC–MS/MS) are: 1) separation of mostly derivatized analytes in the lumen of temperature-programmed gas chromatography (GC) fused-silica capillary columns, 2) ionization of gaseous charge-free analyte derivatives in the ion-source by means of electrons (electron ionization, EI) or in combination with a reagent gas such as methane (chemical ionization, CI), and 3) separation of simply ionized analytes or fragments in electric and/or magnetic fields due to their mass-to-charge ratio (&lt;em&gt;m/z&lt;/em&gt;). EI generates (radical) cations, whereas CI is used to analyze either simply positively (positive-ion chemical ionization, PICI) or simply negatively charged analytes (negative-ion chemical ionization, NICI). In general, NICI in combination with the use of fluorinated (F) derivatization reagents is used in quantitative analyses as fluorinated analytes are softly ionized thus producing anions in high abundance and of high intensity. In quantitative analyses by GC-NICI-MS and GC-NICI-MS/MS, the position of the negative charge in the detected anions is secondary and in many cases unknown. The question of the position of the negative charge in analyte anions formed by NICI in GC-MS and GC-MS/MS is basically of theoretical interest and poorly addresed. The present article discusses this issue in detail. Previously reported GC-NICI-MS and GC-NICI-MS/MS quantitative methods for different classes of analytes, such as amino acids, fatty acids and drugs alongside their &lt;sup&gt;2&lt;/sup&gt;H-, &lt;sup&gt;13&lt;/sup&gt;C-, &lt;sup&gt;15&lt;/sup&gt;N- and &lt;sup&gt;18&lt;/sup&gt;O-isotopologs, after derivatization with fluorinated reagents including pentafluorobenzyl bromide (PFB-Br), pentafluorobenzoyl chloride (PFB-COCl) and pentafluoropropionic anhydride (PFPA) serve as examples and resources of data. ChemDraw Professional software was used to construct chemical structures of analytes and ions found in GC-NICI-MS and GC-NICI-MS/MS mass spectra. The results of the present study provide unique insights into the gas-phase reactions that take place in the ion-source of GC-MS and in the collision-chamber of GC-MS/MS instruments mainly based on the quadrupole (Q) technology. Paradoxically, the negative charge cannot be always assigned in precursor and product ions by standard rules of chemistry, unlike in EI and PICI. For example, PFB esters of fatty acids and eicosanoids (R-COO-PFB) ionize to form their carboxylates with the negative charge being definetly located in the carboxylic groups (R-COO&lt;sup&gt;−&lt;/sup&gt;, [M-PFB]&lt;sup&gt;−&lt;/sup&gt;). In contrast, methyl ester pentafluoropropionyl derivatives of amino acids ionize readily and abundantly under NICI conditions, yet the negative charge cannot be always asigned with apodictic certainty, even not for the calibrating/tuning compound perfluorotributylamine (PFTBA). The &lt;em&gt;paradox&lt;/em&gt; vanishes when considering gas-phase reactions in the ion-source ","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124487"},"PeriodicalIF":2.8,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Anion exchange chromatography coupled to mass spectrometry for deciphering the complexity of a highly glycosylated fusion protein (“protein HGF”)
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-27 DOI: 10.1016/j.jchromb.2025.124484
Florian Füssl , Keith Coleman , Jonathan Bones
Fc-fusion proteins are medicines developed for the treatment of complex diseases which feature enhanced pharmacokinetic properties compared to other therapeutic protein formats. A commonly used strategy for the extension of protein half-life in circulation is the introduction of negative charges on the protein, preferably through N- and O-glycans equipped with negatively charged sialic acid moieties. While enhancing pharmacokinetics, the presence of many glycosylation sites can coincide with a considerable protein heterogeneity, which renders analytical characterisation increasingly difficult. In this work, we demonstrate that the complexity of a highly glycosylated intact Fc-fusion protein can be well resolved using mass spectrometry (MS)-friendly anion exchange chromatography (AEX) with pH gradient elution. The application of the developed method allowed for the separation of 9 clear chromatographic peaks and the acquisition of high-quality protein spectra and thus, MS detection of intact protein isoforms. The resulting data enabled the identification of 268 protein features which represents a ∼ 25-fold increase in detected forms compared to output that could be obtained by simple size exclusion chromatography-mass spectrometry. The underlying cause for the separation selectivity observed in AEX was found to be differential protein sialylation while varying numbers of hexose and N-acetylglucosamine units on glycans were identified as other major contributors to the high heterogeneity observed.
{"title":"Anion exchange chromatography coupled to mass spectrometry for deciphering the complexity of a highly glycosylated fusion protein (“protein HGF”)","authors":"Florian Füssl ,&nbsp;Keith Coleman ,&nbsp;Jonathan Bones","doi":"10.1016/j.jchromb.2025.124484","DOIUrl":"10.1016/j.jchromb.2025.124484","url":null,"abstract":"<div><div>Fc-fusion proteins are medicines developed for the treatment of complex diseases which feature enhanced pharmacokinetic properties compared to other therapeutic protein formats. A commonly used strategy for the extension of protein half-life in circulation is the introduction of negative charges on the protein, preferably through N- and O-glycans equipped with negatively charged sialic acid moieties. While enhancing pharmacokinetics, the presence of many glycosylation sites can coincide with a considerable protein heterogeneity, which renders analytical characterisation increasingly difficult. In this work, we demonstrate that the complexity of a highly glycosylated intact Fc-fusion protein can be well resolved using mass spectrometry (MS)-friendly anion exchange chromatography (AEX) with pH gradient elution. The application of the developed method allowed for the separation of 9 clear chromatographic peaks and the acquisition of high-quality protein spectra and thus, MS detection of intact protein isoforms. The resulting data enabled the identification of 268 protein features which represents a ∼ 25-fold increase in detected forms compared to output that could be obtained by simple size exclusion chromatography-mass spectrometry. The underlying cause for the separation selectivity observed in AEX was found to be differential protein sialylation while varying numbers of hexose and <em>N</em>-acetylglucosamine units on glycans were identified as other major contributors to the high heterogeneity observed.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1254 ","pages":"Article 124484"},"PeriodicalIF":2.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143272981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A novel range-divided data dependent acquisition strategy for screening of diterpenoid alkaloids in Aconitum pendulum roots 一种新颖的范围划分数据依赖采集策略,用于筛选摆尾草根中的二萜生物碱。
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-27 DOI: 10.1016/j.jchromb.2025.124486
Mei Deng , Bishi Ren , Jiayi Yi , Hui Ding , Hua Wang
A novel range-divided data dependent acquisition (DDA) strategy was proposed for the screening of diterpenoid alkaloids in Aconitum pendulum roots. In range-divided DDA, the low-range was set between m/z 340–500 and the high-range was set between m/z 500–700 according to the molecular weight range of the diterpenoid alkaloids. The combined identification approach including MS1 molecular weight, MS2 spectrum interpretation, literature comparison, and standard verification was applied to the results. The range-divided DDA identified 15 more diterpenoid alkaloids than the full-range DDA under the same LC conditions. A total of 47 diterpenoid alkaloids were identified. Among them, brachyaconitines A-D were screened for the first time in Aconitum pendulum. This screening strategy can serve as a powerful tool for the discovery of novel metabolites in the field of plant metabolomics.
{"title":"A novel range-divided data dependent acquisition strategy for screening of diterpenoid alkaloids in Aconitum pendulum roots","authors":"Mei Deng ,&nbsp;Bishi Ren ,&nbsp;Jiayi Yi ,&nbsp;Hui Ding ,&nbsp;Hua Wang","doi":"10.1016/j.jchromb.2025.124486","DOIUrl":"10.1016/j.jchromb.2025.124486","url":null,"abstract":"<div><div>A novel range-divided data dependent acquisition (DDA) strategy was proposed for the screening of diterpenoid alkaloids in <em>Aconitum pendulum</em> roots. In range-divided DDA, the low-range was set between <em>m</em>/<em>z</em> 340–500 and the high-range was set between m/z 500–700 according to the molecular weight range of the diterpenoid alkaloids. The combined identification approach including MS<sup>1</sup> molecular weight, MS<sup>2</sup> spectrum interpretation, literature comparison, and standard verification was applied to the results. The range-divided DDA identified 15 more diterpenoid alkaloids than the full-range DDA under the same LC conditions. A total of 47 diterpenoid alkaloids were identified. Among them, brachyaconitines A-D were screened for the first time in <em>Aconitum pendulum</em>. This screening strategy can serve as a powerful tool for the discovery of novel metabolites in the field of plant metabolomics.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124486"},"PeriodicalIF":2.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143073121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Interaction study between HIV protease inhibitors and alectinib in rats based on an ultra-performance liquid chromatography tandem mass spectrometry method
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-27 DOI: 10.1016/j.jchromb.2025.124483
Yizhang Chen , Ziye Zhou , Yuhan Zeng , Zhongjiang Ye , Rongqi Li , Chuang Chen , Jianhui Yang , Jing Fu , Tao Zhou , Danna Jiang , Sunting Qin , Xiuhua Zhang , Chenxiang Wang
We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to measure alectinib concentrations in rat plasma and use it to investigate the effect of HIV protease inhibitors on the pharmacokinetic parameters of alectinib in rats. Acetonitrile was used to precipitate the samples. We used a BEH C18 column to perform chromatographic separation on a UPLC system. The mobile phase comprised 0.1 % formic acid, water, and acetonitrile. Mass spectrometry analysis was conducted using a Xevo TQ-Striple quadrupole tandem mass spectrometer. Alectinib and lorlatinib (internal standard) were measured in MRM mode. The fragment ions were 483.2-396.1 for alectinib and m/z 407.3-228.1 for lorlatinib. The validated UPLC-MS/MS method was used to study drug interactions of atazanavir, darunavir, indinavir, and ritonavir with alectinib in rat plasma. We found atazanavir, darunavir, indinavir, and ritonavir significantly inhibited alectinib metabolism. When administered with atazanavir, darunavir, indinavir, and ritonavir, the AUC0-t of alectinib increased by 94.0 %, 175.7 %, 220.9 %, and 62.4 %, respectively; the clearance of alectinib decreased by 53.4 %, 63.6 %, 67.8 %, and 41.1 %, respectively. In short, we developed an UPLC-MS/MS approach to measure alectinib in rat plasma. Atazanavir, darunavir, indinavir, and ritonavir dramatically inhibited alectinib metabolism. The dosages should be adjusted when using atazanavir, darunavir, indinavir, and ritonavir with alectinib. Real-time monitoring should occur during treatment.
{"title":"Interaction study between HIV protease inhibitors and alectinib in rats based on an ultra-performance liquid chromatography tandem mass spectrometry method","authors":"Yizhang Chen ,&nbsp;Ziye Zhou ,&nbsp;Yuhan Zeng ,&nbsp;Zhongjiang Ye ,&nbsp;Rongqi Li ,&nbsp;Chuang Chen ,&nbsp;Jianhui Yang ,&nbsp;Jing Fu ,&nbsp;Tao Zhou ,&nbsp;Danna Jiang ,&nbsp;Sunting Qin ,&nbsp;Xiuhua Zhang ,&nbsp;Chenxiang Wang","doi":"10.1016/j.jchromb.2025.124483","DOIUrl":"10.1016/j.jchromb.2025.124483","url":null,"abstract":"<div><div>We established an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method to measure alectinib concentrations in rat plasma and use it to investigate the effect of HIV protease inhibitors on the pharmacokinetic parameters of alectinib in rats. Acetonitrile was used to precipitate the samples. We used a BEH C18 column to perform chromatographic separation on a UPLC system. The mobile phase comprised 0.1 % formic acid, water, and acetonitrile. Mass spectrometry analysis was conducted using a Xevo TQ-Striple quadrupole tandem mass spectrometer. Alectinib and lorlatinib (internal standard) were measured in MRM mode. The fragment ions were 483.2-396.1 for alectinib and <em>m</em>/<em>z</em> 407.3-228.1 for lorlatinib. The validated UPLC-MS/MS method was used to study drug interactions of atazanavir, darunavir, indinavir, and ritonavir with alectinib in rat plasma. We found atazanavir, darunavir, indinavir, and ritonavir significantly inhibited alectinib metabolism. When administered with atazanavir, darunavir, indinavir, and ritonavir, the AUC<sub>0-t</sub> of alectinib increased by 94.0 %, 175.7 %, 220.9 %, and 62.4 %, respectively; the clearance of alectinib decreased by 53.4 %, 63.6 %, 67.8 %, and 41.1 %, respectively. In short, we developed an UPLC-MS/MS approach to measure alectinib in rat plasma. Atazanavir, darunavir, indinavir, and ritonavir dramatically inhibited alectinib metabolism. The dosages should be adjusted when using atazanavir, darunavir, indinavir, and ritonavir with alectinib. Real-time monitoring should occur during treatment.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124483"},"PeriodicalIF":2.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143078302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Analytical and clinical validation of a volumetric absorptive microsampling (VAMS) – Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the analysis of Clofazimine in whole blood
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-25 DOI: 10.1016/j.jchromb.2025.124482
Rhea Veda Nugraha , Vycke Yunivita , Prayudi Santoso , Aliya Nur Hasanah , Triana Nurul Meirina , Atu Purnama Dewi , Harold Eka Atmaja , Lindsey te Brake , Rob E. Aarnoutse , Rovina Ruslami
Monitoring clofazimine blood concentrations is crucial for preventing treatment failure in patients with Multidrug-resistant Tuberculosis (MDR-TB). Volumetric Absorptive Microsampling (VAMS) offers a practical alternative to Conventional Venous Sampling (CVS), enabling remote sampling. Samples collected via VAMS can be conveniently transported to laboratories via courier, enhancing accessibility and patient compliance. In this study, we developed and validated an analytical method for quantifying clofazimine in whole blood collected using VAMS. The study compared the performance and cost-effectiveness of VAMS with CVS. A total of 55 matched finger-prick VAMS and CVS samples were obtained from 39 MDR-TB patients and analyzed using validated UPLC-MS/MS assays. Clofazimine concentrations collected via VAMS and CVS were compared using Passing-Bablok regression, while bias and overall agreement were evaluated through Bland-Altman analysis. Passing-Bablok regression revealed no significant constant difference between VAMS and CVS (95% CI slope: 0.7627–0.9573; 95% CI intercept: −0.02141–0.06482), but systematic difference of 13% lower clofazimine concentrations was observed in VAMS compared to plasma. Bland-Altman analysis demonstrated moderate agreement, with mean plasma/VAMS ratio of 0.9457 (95% CI: 0.88358–1.00775) and 95% Limits of Agreement (LoA) ranging from 0.4956 (95% CI: 0.38881–0.60230) to 1.3858 (95% CI: 1.28903–1.50252). Although statistically significant bias was identified, applying correction factors could improve interchangeability between the two techniques. Furthermore, VAMS was more cost-effective than CVS, with approximate cost difference of 4.45 USD per sample. These findings suggest that VAMS sampling has the potential to replace CVS for routine clinical monitoring of clofazimine, offering a more accessible and economical approach.
{"title":"Analytical and clinical validation of a volumetric absorptive microsampling (VAMS) – Ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method for the analysis of Clofazimine in whole blood","authors":"Rhea Veda Nugraha ,&nbsp;Vycke Yunivita ,&nbsp;Prayudi Santoso ,&nbsp;Aliya Nur Hasanah ,&nbsp;Triana Nurul Meirina ,&nbsp;Atu Purnama Dewi ,&nbsp;Harold Eka Atmaja ,&nbsp;Lindsey te Brake ,&nbsp;Rob E. Aarnoutse ,&nbsp;Rovina Ruslami","doi":"10.1016/j.jchromb.2025.124482","DOIUrl":"10.1016/j.jchromb.2025.124482","url":null,"abstract":"<div><div>Monitoring clofazimine blood concentrations is crucial for preventing treatment failure in patients with Multidrug-resistant Tuberculosis (MDR-TB). Volumetric Absorptive Microsampling (VAMS) offers a practical alternative to Conventional Venous Sampling (CVS), enabling remote sampling. Samples collected via VAMS can be conveniently transported to laboratories via courier, enhancing accessibility and patient compliance. In this study, we developed and validated an analytical method for quantifying clofazimine in whole blood collected using VAMS. The study compared the performance and cost-effectiveness of VAMS with CVS. A total of 55 matched finger-prick VAMS and CVS samples were obtained from 39 MDR-TB patients and analyzed using validated UPLC-MS/MS assays. Clofazimine concentrations collected via VAMS and CVS were compared using Passing-Bablok regression, while bias and overall agreement were evaluated through Bland-Altman analysis. Passing-Bablok regression revealed no significant constant difference between VAMS and CVS (95% CI slope: 0.7627–0.9573; 95% CI intercept: −0.02141–0.06482), but systematic difference of 13% lower clofazimine concentrations was observed in VAMS compared to plasma. Bland-Altman analysis demonstrated moderate agreement, with mean plasma/VAMS ratio of 0.9457 (95% CI: 0.88358–1.00775) and 95% Limits of Agreement (LoA) ranging from 0.4956 (95% CI: 0.38881–0.60230) to 1.3858 (95% CI: 1.28903–1.50252). Although statistically significant bias was identified, applying correction factors could improve interchangeability between the two techniques. Furthermore, VAMS was more cost-effective than CVS, with approximate cost difference of 4.45 USD per sample. These findings suggest that VAMS sampling has the potential to replace CVS for routine clinical monitoring of clofazimine, offering a more accessible and economical approach.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124482"},"PeriodicalIF":2.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143121916","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Experimental and computational analysis of lipophilicity and plasma protein binding properties of potent tacrine based cholinesterase inhibitors
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-25 DOI: 10.1016/j.jchromb.2025.124481
Sandra Šegan , Mirjana Mosić , Vladimir Šukalović , Ivana Jevtić
The lipophilicity of thirteen tacrine/piperidine-4-carboxamide derivatives was assessed using reversed-phase thin-layer chromatography (RP-TLC) with MeOH and acetonitrile (ACN) as organic modifiers. Among the parameters evaluated, the RM0 and C0 values obtained using MeOH were identified as the most reliable for characterizing the lipophilicity of the investigated compounds. The observed differences in lipophilicity among the derivatives resulted from a delicate interplay of substituent effects (hydrophobicity, polarity, steric hindrance, and electronic effects), positional influence, and characteristics of the organic modifier.
The plasma protein-binding (PPB) properties of the tacrine derivatives were analyzed using an HPLC method with a human serum albumin (HSA) stationary phase and a mobile phase composed of phosphate buffer (pH = 7) and 2-propanol. The experimental %PPB values calculated using from two experiments ranged from 82.38 % to 94.54 %, and 84.29 % to 98.16 % suggesting that most compounds bind efficiently but not excessively to plasma proteins.
Docking analysis revealed that all investigated ligands bind to Sudlow site I within HSA, which is the main binding site for heterocyclic aromatic compounds such as warfarine, azoprazone and tacrine. The key binding interactions are primarily hydrogen bonding and aromatic interactions.
Principal component analysis (PCA), conducted on both experimentally determined and predicted lipophilicity values, as well as on predicted adsorption and experimentally and predicted distribution data, underscored the significant role of lipophilicity in influencing adsorption and distribution processes.
{"title":"Experimental and computational analysis of lipophilicity and plasma protein binding properties of potent tacrine based cholinesterase inhibitors","authors":"Sandra Šegan ,&nbsp;Mirjana Mosić ,&nbsp;Vladimir Šukalović ,&nbsp;Ivana Jevtić","doi":"10.1016/j.jchromb.2025.124481","DOIUrl":"10.1016/j.jchromb.2025.124481","url":null,"abstract":"<div><div>The lipophilicity of thirteen tacrine/piperidine-4-carboxamide derivatives was assessed using reversed-phase thin-layer chromatography (RP-TLC) with MeOH and acetonitrile (ACN) as organic modifiers. Among the parameters evaluated, the R<sub>M</sub><sup>0</sup> and C<sup>0</sup> values obtained using MeOH were identified as the most reliable for characterizing the lipophilicity of the investigated compounds. The observed differences in lipophilicity among the derivatives resulted from a delicate interplay of substituent effects (hydrophobicity, polarity, steric hindrance, and electronic effects), positional influence, and characteristics of the organic modifier.</div><div>The plasma protein-binding (PPB) properties of the tacrine derivatives were analyzed using an HPLC method with a human serum albumin (HSA) stationary phase and a mobile phase composed of phosphate buffer (pH = 7) and 2-propanol. The experimental %PPB values calculated using from two experiments ranged from 82.38 % to 94.54 %, and 84.29 % to 98.16 % suggesting that most compounds bind efficiently but not excessively to plasma proteins.</div><div>Docking analysis revealed that all investigated ligands bind to Sudlow site I within HSA, which is the main binding site for heterocyclic aromatic compounds such as warfarine, azoprazone and tacrine. The key binding interactions are primarily hydrogen bonding and aromatic interactions.</div><div>Principal component analysis (PCA), conducted on both experimentally determined and predicted lipophilicity values, as well as on predicted adsorption and experimentally and predicted distribution data, underscored the significant role of lipophilicity in influencing adsorption and distribution processes.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124481"},"PeriodicalIF":2.8,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Preparation of the immobilized α1A-adrenoceptor column by the ultra-high affinity protein pair CL7/Im7 and its application in drug-protein interaction analysis
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-24 DOI: 10.1016/j.jchromb.2025.124478
Qiuyu Gao , Shuangru Wan , Xinchao Cao , Yao Chen , Ning Wang , Xia Wang , Yue Ma , Di Zhang , Jing Wang , Dalong Zhi
Immobilizing the target protein on a solid surface with controlled orientation, high specificity, and maintained activity is a proven strategy to enhance the stability of the protein. In this study, we employed an ultra-high affinity protein pair consisting of a mutant of colicin E7 Dnase and its corresponding inhibitor, immunity protein 7(Im7), to develop an immobilized α1A-adrenoceptor (α1A-AR) column. Briefly, we expressed α1A-AR fused with CL7 as a tag at its C-terminus in Escherichia coli cells. Meanwhile, we got His-tagged Im7 at the same manner. Following purification, the His-tagged Im7 was utilized to functionalize the macro-porous silica gel. Leveraging the ultra-high affinity between the protein pair, we achieved robust and specific covalent immobilization of α1A-AR covalently at ambient conditions in buffer solutions, without the requirement for additional regents. The successful immobilization of the receptor, without extraneous protein adsorption, was confirmed through X ray photoelectron spectroscopy and chromatographic investigations. Frontal analysis and adsorption energy distribution analysis further validated the feasibility of the immobilization method. Our findings align well with those reported in the literature. This work is poised to provide a modular platform for conducting effective investigations into the binding interactions between other functional proteins and the drugs.
{"title":"Preparation of the immobilized α1A-adrenoceptor column by the ultra-high affinity protein pair CL7/Im7 and its application in drug-protein interaction analysis","authors":"Qiuyu Gao ,&nbsp;Shuangru Wan ,&nbsp;Xinchao Cao ,&nbsp;Yao Chen ,&nbsp;Ning Wang ,&nbsp;Xia Wang ,&nbsp;Yue Ma ,&nbsp;Di Zhang ,&nbsp;Jing Wang ,&nbsp;Dalong Zhi","doi":"10.1016/j.jchromb.2025.124478","DOIUrl":"10.1016/j.jchromb.2025.124478","url":null,"abstract":"<div><div>Immobilizing the target protein on a solid surface with controlled orientation, high specificity, and maintained activity is a proven strategy to enhance the stability of the protein. In this study, we employed an ultra-high affinity protein pair consisting of a mutant of colicin E7 Dnase and its corresponding inhibitor, immunity protein 7(Im7), to develop an immobilized α<sub>1A</sub>-adrenoceptor (α<sub>1A</sub>-AR) column. Briefly, we expressed α<sub>1A</sub>-AR fused with CL7 as a tag at its C-terminus in <em>Escherichia coli</em> cells. Meanwhile, we got His-tagged Im7 at the same manner. Following purification, the His-tagged Im7 was utilized to functionalize the macro-porous silica gel. Leveraging the ultra-high affinity between the protein pair, we achieved robust and specific covalent immobilization of α<sub>1A</sub>-AR covalently at ambient conditions in buffer solutions, without the requirement for additional regents. The successful immobilization of the receptor, without extraneous protein adsorption, was confirmed through X ray photoelectron spectroscopy and chromatographic investigations. Frontal analysis and adsorption energy distribution analysis further validated the feasibility of the immobilization method. Our findings align well with those reported in the literature. This work is poised to provide a modular platform for conducting effective investigations into the binding interactions between other functional proteins and the drugs.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124478"},"PeriodicalIF":2.8,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063041","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Potential for application of direct thrombin inhibitors isolated from Euphorbia resinifera O.Berg latex in fibrin clot formation
IF 2.8 3区 医学 Q2 BIOCHEMICAL RESEARCH METHODS Pub Date : 2025-01-23 DOI: 10.1016/j.jchromb.2025.124480
Jaruwan Siritapetawee , Yanling Hua , Chutima Talabnin , Nopporn Naewwan , Ratana Charoenwattanasatien , Chalermluck Phoovasawat , Supawan Srichan , Chortip Kantachot
Direct thrombin inhibitors (designated as EuRL-DTIs) were partially purified from ethanol extracts of Euphorbia resinifera O.Berg latex. The obtained EuRL-DTIs comprised four major compounds: two isomers of phenolic compounds (C19H26O12) and two amide compounds (tentatively identified as C24H44N4O4 and C36H66N6O6), as identified by liquid chromatography and electrospray ionisation quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS/MS), attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, and/or nuclear magnetic resonance (NMR) spectroscopy. The effects of EuRL-DTIs on human thrombin-induced fibrin clot production were analysed using thrombin time, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), synchrotron radiation X-ray tomographic microscopy (SRXTM), and scanning electron microscopy (SEM). Kinetic studies revealed that EuRL-DTIs inhibited human thrombin from cleaving the chromogenic substrate S2238, with a Ki of 3.7 μg/mL, in a non-competitive inhibition manner. All results supported the hypothesis that the EuRL-DTIs directly abolished thrombin activity in the production of fibrin clots without requiring a cofactor. The cytotoxicity test showed that EuRL-DTIs were nontoxic to normal human foetal lung fibroblasts (IMR-90). Thus, EuRL-DTIs have potential as antithrombotic agents for application as drugs for thrombosis treatments or in medical devices such as coating surgical sutures.
{"title":"Potential for application of direct thrombin inhibitors isolated from Euphorbia resinifera O.Berg latex in fibrin clot formation","authors":"Jaruwan Siritapetawee ,&nbsp;Yanling Hua ,&nbsp;Chutima Talabnin ,&nbsp;Nopporn Naewwan ,&nbsp;Ratana Charoenwattanasatien ,&nbsp;Chalermluck Phoovasawat ,&nbsp;Supawan Srichan ,&nbsp;Chortip Kantachot","doi":"10.1016/j.jchromb.2025.124480","DOIUrl":"10.1016/j.jchromb.2025.124480","url":null,"abstract":"<div><div>Direct thrombin inhibitors (designated as EuRL-DTIs) were partially purified from ethanol extracts of <em>Euphorbia resinifera</em> O.Berg latex. The obtained EuRL-DTIs comprised four major compounds: two isomers of phenolic compounds (C<sub>19</sub>H<sub>26</sub>O<sub>12</sub>) and two amide compounds (tentatively identified as C<sub>24</sub>H<sub>44</sub>N<sub>4</sub>O<sub>4</sub> and C<sub>36</sub>H<sub>66</sub>N<sub>6</sub>O<sub>6</sub>), as identified by liquid chromatography and electrospray ionisation quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS/MS), attenuated total reflection-Fourier transform infrared (ATR-FTIR) spectroscopy, and/or nuclear magnetic resonance (NMR) spectroscopy. The effects of EuRL-DTIs on human thrombin-induced fibrin clot production were analysed using thrombin time, sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), synchrotron radiation X-ray tomographic microscopy (SRXTM), and scanning electron microscopy (SEM). Kinetic studies revealed that EuRL-DTIs inhibited human thrombin from cleaving the chromogenic substrate S2238, with a <em>K</em><sub>i</sub> of 3.7 μg/mL, in a non-competitive inhibition manner. All results supported the hypothesis that the EuRL-DTIs directly abolished thrombin activity in the production of fibrin clots without requiring a cofactor. The cytotoxicity test showed that EuRL-DTIs were nontoxic to normal human foetal lung fibroblasts (IMR-90). Thus, EuRL-DTIs have potential as antithrombotic agents for application as drugs for thrombosis treatments or in medical devices such as coating surgical sutures.</div></div>","PeriodicalId":348,"journal":{"name":"Journal of Chromatography B","volume":"1253 ","pages":"Article 124480"},"PeriodicalIF":2.8,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143063039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Journal of Chromatography B
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