The Experts below are selected from a list of 32031 Experts worldwide ranked by ideXlab platform
Mingshe Zhu - One of the best experts on this subject based on the ideXlab platform.
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mass defect filter technique and its applications to Drug Metabolite identification by high resolution mass spectrometry
Journal of Mass Spectrometry, 2009Co-Authors: Haiying Zhang, Donglu Zhang, Kenneth Ray, Mingshe ZhuAbstract:Identification of Drug Metabolites by liquid chromatography/mass spectrometry (LC/MS) involves Metabolite detection in biological matrixes and structural characterization based on product ion spectra. Traditionally, Metabolite detection is accomplished primarily on the basis of predicted molecular masses or fragmentation patterns of Metabolites using triple-quadrupole and ion trap mass spectrometers. Recently, a novel mass defect filter (MDF) technique has been developed, which enables high-resolution mass spectrometers to be utilized for detecting both predicted and unexpected Drug Metabolites based on narrow, well-defined mass defect ranges for these Metabolites. This is a new approach that is completely different from, but complementary to, traditional molecular mass- or MS/MS fragmentation-based LC/MS approaches. This article reviews the mass defect patterns of various classes of Drug Metabolites and the basic principles of the MDF approach. Examples are given on the applications of the MDF technique to the detection of stable and chemically reactive Metabolites in vitro and in vivo. Advantages, limitations, and future applications are also discussed on MDF and its combinations with other data mining techniques for the detection and identification of Drug Metabolites.
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rapid screening and characterization of Drug Metabolites using multiple ion monitoring dependent product ion scan and postacquisition data mining on a hybrid triple quadrupole linear ion trap mass spectrometer
Rapid Communications in Mass Spectrometry, 2009Co-Authors: Ming Yao, Eva Duchoslav, Mingshe ZhuAbstract:Multiple ion monitoring (MIM)-dependent acquisition with a triple quadrupole-linear ion trap mass spectrometer (Q-trap) was previously developed for Drug Metabolite profiling. In the analysis, multiple predicted Metabolite ions are monitored in both Q1 and Q3 regardless of their fragmentations. The collision energy in Q2 is set to a low value to minimize fragmentation. Once an expected Metabolite is detected by MIM, enhanced product ion (EPI) spectral acquisition of the Metabolite is triggered. To analyze in vitro Metabolites, MIM-EPI retains the sensitivity and selectivity similar to that of multiple reaction monitoring (MRM)-EPI in the analysis of in vitro Metabolites. Here we present an improved approach utilizing MIM-EPI for data acquisition and multiple data mining techniques for detection of Metabolite ions and recovery of their MS/MS spectra. The postacquisition data processing tools included extracted ion chromatographic analysis, product ion filtering and neutral loss filtering. The effectiveness of this approach was evaluated by analyzing oxidative Metabolites of indinavir and glutathione (GSH) conjugates of clozapine and 4-ethylphenol in liver microsome incubations. Results showed that the MIM-EPI-based data mining approach allowed for comprehensive detection of Metabolites based on predicted protonated molecules, product ions or neutral losses without predetermination of the parent Drug MS/MS spectra. Additionally, it enabled Metabolite detection and MS/MS acquisition in a single injection. This approach is potentially useful in high-throughout screening of metabolic soft spots and reactive Metabolites at the Drug discovery stage.
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rapid screening and characterization of Drug Metabolites using a multiple ion monitoring dependent ms ms acquisition method on a hybrid triple quadrupole linear ion trap mass spectrometer
Journal of Mass Spectrometry, 2008Co-Authors: Ming Yao, Griffith W Humphreys, Mingshe ZhuAbstract:A novel LC/MS/MS method that uses multiple ion monitoring (MIM) as a survey scan to trigger the acquisition of enhanced product ions (EPI) on a hybrid quadrupole-linear ion trap mass spectrometer (Q TRAP) was developed for Drug Metabolite identification. In the MIM experiment, multiple predicted Metabolite ions were monitored in both Q1 and Q3. The collision energy in Q2 was set to a low value to minimize fragmentation. Results from analyzing ritonavir Metabolites in rat hepatocytes demonstrate that MIM-EPI was capable of targeting a larger number of Metabolites regardless of their fragmentation and retained sensitivity and duty cycle similar to multiple reaction monitoring (MRM)-EPI. MIM-based scanning methods were shown to be particularly useful in several applications. First, MIM-EPI enabled the sensitive detection and MS/MS acquisition of up to 100 predicted Metabolites. Second, MIM-MRM-EPI was better than MRM-EPI in the analysis of Metabolites that undergo either predictable or unpredictable fragmentation pathways. Finally, a combination of MIM-EPI and full-scan MS (EMS), as an alternative to EMS-EPI, was well suited for routine in vitro Metabolite profiling. Overall, MIM-EPI significantly enhanced the Metabolite identification capability of the hybrid triple quadrupole-linear ion trap LC/MS.
Ming Yao - One of the best experts on this subject based on the ideXlab platform.
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rapid screening and characterization of Drug Metabolites using multiple ion monitoring dependent product ion scan and postacquisition data mining on a hybrid triple quadrupole linear ion trap mass spectrometer
Rapid Communications in Mass Spectrometry, 2009Co-Authors: Ming Yao, Eva Duchoslav, Mingshe ZhuAbstract:Multiple ion monitoring (MIM)-dependent acquisition with a triple quadrupole-linear ion trap mass spectrometer (Q-trap) was previously developed for Drug Metabolite profiling. In the analysis, multiple predicted Metabolite ions are monitored in both Q1 and Q3 regardless of their fragmentations. The collision energy in Q2 is set to a low value to minimize fragmentation. Once an expected Metabolite is detected by MIM, enhanced product ion (EPI) spectral acquisition of the Metabolite is triggered. To analyze in vitro Metabolites, MIM-EPI retains the sensitivity and selectivity similar to that of multiple reaction monitoring (MRM)-EPI in the analysis of in vitro Metabolites. Here we present an improved approach utilizing MIM-EPI for data acquisition and multiple data mining techniques for detection of Metabolite ions and recovery of their MS/MS spectra. The postacquisition data processing tools included extracted ion chromatographic analysis, product ion filtering and neutral loss filtering. The effectiveness of this approach was evaluated by analyzing oxidative Metabolites of indinavir and glutathione (GSH) conjugates of clozapine and 4-ethylphenol in liver microsome incubations. Results showed that the MIM-EPI-based data mining approach allowed for comprehensive detection of Metabolites based on predicted protonated molecules, product ions or neutral losses without predetermination of the parent Drug MS/MS spectra. Additionally, it enabled Metabolite detection and MS/MS acquisition in a single injection. This approach is potentially useful in high-throughout screening of metabolic soft spots and reactive Metabolites at the Drug discovery stage.
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rapid screening and characterization of Drug Metabolites using a multiple ion monitoring dependent ms ms acquisition method on a hybrid triple quadrupole linear ion trap mass spectrometer
Journal of Mass Spectrometry, 2008Co-Authors: Ming Yao, Griffith W Humphreys, Mingshe ZhuAbstract:A novel LC/MS/MS method that uses multiple ion monitoring (MIM) as a survey scan to trigger the acquisition of enhanced product ions (EPI) on a hybrid quadrupole-linear ion trap mass spectrometer (Q TRAP) was developed for Drug Metabolite identification. In the MIM experiment, multiple predicted Metabolite ions were monitored in both Q1 and Q3. The collision energy in Q2 was set to a low value to minimize fragmentation. Results from analyzing ritonavir Metabolites in rat hepatocytes demonstrate that MIM-EPI was capable of targeting a larger number of Metabolites regardless of their fragmentation and retained sensitivity and duty cycle similar to multiple reaction monitoring (MRM)-EPI. MIM-based scanning methods were shown to be particularly useful in several applications. First, MIM-EPI enabled the sensitive detection and MS/MS acquisition of up to 100 predicted Metabolites. Second, MIM-MRM-EPI was better than MRM-EPI in the analysis of Metabolites that undergo either predictable or unpredictable fragmentation pathways. Finally, a combination of MIM-EPI and full-scan MS (EMS), as an alternative to EMS-EPI, was well suited for routine in vitro Metabolite profiling. Overall, MIM-EPI significantly enhanced the Metabolite identification capability of the hybrid triple quadrupole-linear ion trap LC/MS.
Lawrence Vernetti - One of the best experts on this subject based on the ideXlab platform.
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functional coupling of human microphysiology systems intestine liver kidney proximal tubule blood brain barrier and skeletal muscle
Scientific Reports, 2017Co-Authors: Lawrence Vernetti, Sarah Blutt, Jacquelyn A. Brown, Nesrin Hasan, Albert Gough, James R. Broughman, Nicholas W Baetz, Jennifer Foulkeabel, Edward J Kelly, Olga KovbasnjukAbstract:Organ interactions resulting from Drug, Metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of Drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the Drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome Metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.
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Corrigendum: Functional Coupling of Human Microphysiology Systems: Intestine, Liver, Kidney Proximal Tubule, Blood-Brain Barrier and Skeletal Muscle
Scientific reports, 2017Co-Authors: Lawrence Vernetti, Nicholas Baetz, Sarah Blutt, Jacquelyn A. Brown, Jennifer Foulke-abel, Nesrin Hasan, Julie In, Albert Gough, James R. Broughman, Edward KellyAbstract:Organ interactions resulting from Drug, Metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of Drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the Drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome Metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.
Hans H Maurer - One of the best experts on this subject based on the ideXlab platform.
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biotechnological synthesis of the designer Drug Metabolite 4 hydroxymethyl α pyrrolidinohexanophenone in fission yeast heterologously expressing human cytochrome p450 2d6 a versatile alternative to multistep chemical synthesis
Journal of Analytical Toxicology, 2009Co-Authors: Frank T Peters, Josef Zapp, Matthias Bureik, Calinaurel Dragan, Anne Kauffels, Andrea E Schwaninger, Hans H MaurerAbstract:: 1-(4-Methylphenyl)-2-pyrrolidin-1-ylhexan-1-one (4'-methyl-alpha-pyrrolidinohexanophenone, MPHP) is a new designer Drug that appeared on the illicit Drug market. It is mainly metabolized to 4'-hydroxymethyl-alpha-pyrrolidinohexanophenone (HO-MPHP) followed by oxidation to the respective carboxylic acid. For studies on the quantitative involvement of human cytochrome P450 (CYP) isoenzymes in the initial hydroxylation, a reference standard of HO-MPHP was needed. Therefore, the aim of this study was to synthesize this Metabolite using a biotechnological approach. MPHP.HNO(3) (250 micromol) was incubated with 1 L culture of the fission yeast (Schizosaccharomyces pombe) strain CAD64 heterologously co-expressing human CYP reductase and CYP2D6. After centrifugation, the product was isolated from the incubation supernatants by solid-phase extraction. Further product cleanup was achieved by semi-preparative high-performance liquid chromatography (HPLC). After extraction of HO-MPHP from the respective eluent fractions, it was precipitated as its hydrochloric salt. The final product HO-MPHP.HCl was obtained in a yield of 138 micromol (43 mg, 55%). Its identity was confirmed by full scan gas chromatography-mass spectrometry (after trimethylsilylation), (1)H-NMR, and (13)C-NMR. The product purity as estimated from HPLC-ultraviolet analysis was greater than 99%. The described biotechnological approach proved to be a versatile alternative to the chemical synthesis of HO-MPHP.
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biotechnological synthesis of Drug Metabolites using human cytochrome p450 2d6 heterologously expressed in fission yeast exemplified for the designer Drug Metabolite 4 hydroxymethyl α pyrrolidinobutyrophenone
Biochemical Pharmacology, 2007Co-Authors: Frank T Peters, Calina Dragan, Desiree R Wilde, Josef Zapp, Matthias Bureik, Markus R. Meyer, Hans H MaurerAbstract:Abstract The aim of this study was evaluating the principle feasibility of biotechnological synthesis of Drug Metabolites using heterologously expressed human cytochrome P450 (CYP) enzymes. Human CYP2D6 expressed in fission yeast (Schizosaccharomyces pombe) strain CAD58 was used as model enzyme and the designer Drug 4′-methyl-α-pyrrolidinobutyrophenone (MPBP) as model Drug. For synthesis of 4′-hydroxmethyl-α-pyrrolidinobutyrophenone (HO-MPBP), 250 μmol of MPBP·HNO3 were incubated with one litre of CAD58 culture (108 cells/mL, pH 9, 48 h, 30 °C). HO-MPBP was isolated by liquid–liquid extraction and precipitated as its hydrochloride salt. Identity and purity of the product were tested by HPLC with ultraviolet (UV) detection, GC-MS, and 1H-NMR. CAD58 was further characterized regarding the influence of incubation pH (5–10), cell density (107–108 cells/mL), and incubation time (0–120 h) on Metabolite formation using the substrates dextromethorphan and MPBP. The preparative experiment yielded 40 mg (141 μmol) of HO-MPBP·HCl with a purity of >98%. In the characterization experiments, the Metabolite formation rate peaked at pH 8. A linear relationship was observed between cell density and Metabolite formation (R2 > 0.996). The rate of Metabolite formation was slower in the earlier stages of incubation but then increased. For HO-MPBP, it became constant in the time interval of 2.5–34 h (R2 > 998).
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biotechnological synthesis of Drug Metabolites using human cytochrome p450 2d6 heterologously expressed in fission yeast exemplified for the designer Drug Metabolite 4 hydroxymethyl α pyrrolidinobutyrophenone
Biochemical Pharmacology, 2007Co-Authors: Frank T Peters, Calina Dragan, Desiree R Wilde, Josef Zapp, Matthias Bureik, Markus R. Meyer, Hans H MaurerAbstract:The aim of this study was evaluating the principle feasibility of biotechnological synthesis of Drug Metabolites using heterologously expressed human cytochrome P450 (CYP) enzymes. Human CYP2D6 expressed in fission yeast (Schizosaccharomyces pombe) strain CAD58 was used as model enzyme and the designer Drug 4'-methyl-alpha-pyrrolidinobutyrophenone (MPBP) as model Drug. For synthesis of 4'-hydroxmethyl-alpha-pyrrolidinobutyrophenone (HO-MPBP), 250 micromol of MPBP.HNO(3) were incubated with one litre of CAD58 culture (10(8)cells/mL, pH 9, 48 h, 30 degrees C). HO-MPBP was isolated by liquid-liquid extraction and precipitated as its hydrochloride salt. Identity and purity of the product were tested by HPLC with ultraviolet (UV) detection, GC-MS, and (1)H-NMR. CAD58 was further characterized regarding the influence of incubation pH (5-10), cell density (10(7)-10(8)cells/mL), and incubation time (0-120 h) on Metabolite formation using the substrates dextromethorphan and MPBP. The preparative experiment yielded 40 mg (141mumol) of HO-MPBP.HCl with a purity of >98%. In the characterization experiments, the Metabolite formation rate peaked at pH 8. A linear relationship was observed between cell density and Metabolite formation (R(2)>0.996). The rate of Metabolite formation was slower in the earlier stages of incubation but then increased. For HO-MPBP, it became constant in the time interval of 2.5-34 h (R(2)>998).
Olga Kovbasnjuk - One of the best experts on this subject based on the ideXlab platform.
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functional coupling of human microphysiology systems intestine liver kidney proximal tubule blood brain barrier and skeletal muscle
Scientific Reports, 2017Co-Authors: Lawrence Vernetti, Sarah Blutt, Jacquelyn A. Brown, Nesrin Hasan, Albert Gough, James R. Broughman, Nicholas W Baetz, Jennifer Foulkeabel, Edward J Kelly, Olga KovbasnjukAbstract:Organ interactions resulting from Drug, Metabolite or xenobiotic transport between organs are key components of human metabolism that impact therapeutic action and toxic side effects. Preclinical animal testing often fails to predict adverse outcomes arising from sequential, multi-organ metabolism of Drugs and xenobiotics. Human microphysiological systems (MPS) can model these interactions and are predicted to dramatically improve the efficiency of the Drug development process. In this study, five human MPS models were evaluated for functional coupling, defined as the determination of organ interactions via an in vivo-like sequential, organ-to-organ transfer of media. MPS models representing the major absorption, metabolism and clearance organs (the jejunum, liver and kidney) were evaluated, along with skeletal muscle and neurovascular models. Three compounds were evaluated for organ-specific processing: terfenadine for pharmacokinetics (PK) and toxicity; trimethylamine (TMA) as a potentially toxic microbiome Metabolite; and vitamin D3. We show that the organ-specific processing of these compounds was consistent with clinical data, and discovered that trimethylamine-N-oxide (TMAO) crosses the blood-brain barrier. These studies demonstrate the potential of human MPS for multi-organ toxicity and absorption, distribution, metabolism and excretion (ADME), provide guidance for physically coupling MPS, and offer an approach to coupling MPS with distinct media and perfusion requirements.
