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Hartmut Derendorf - One of the best experts on this subject based on the ideXlab platform.
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determination of atypical nonlinear Plasma Protein Binding behavior of tigecycline using an in vitro microdialysis technique
Journal of Pharmaceutical Sciences, 2014Co-Authors: Jatinder Kaur Mukker, Ravishankar Prasad Singh, Hartmut DerendorfAbstract:ABSTRACT Tigecycline, a novel glycylcycline antibiotic, shows atypical nonlinear Plasma–Protein-Binding behavior using ultrafiltration and ultracentrifugation techniques. The mechanism of such counterintuitive behavior is currently unknown. Ultrafiltration and ultracentrifugation cause fractional change in Protein concentration and therefore may influence Plasma–Protein Binding. Microdialysis (MD), a novel technique, can sample unbound drugs without any change in fractional Protein concentration. To determine whether the atypical nonlinear Plasma–Protein-Binding behavior is not related to measurement technique, the Plasma–Protein Binding of tigecycline was determined using MD. A sensitive liquid chromatography-mass spectrometry method was developed and validated for the bioanalysis of tigecycline in the dialysate. The probe recoveries and Plasma–Protein Binding of tigecycline at four different concentration levels 0.1, 1, 10, and 100 μg/mL were determined. Similar to ultracentrifugation and ultrafiltration, MD also showed atypical nonlinear Plasma–Protein-Binding behavior of tigecycline up to 10 μg/mL, but unbound fraction increased at 100 μg/mL indicating saturation of mechanism responsible for atypical nonlinear behavior. This study concludes that the atypical nonlinear Binding behavior of tigecycline is not technique-dependent, rather it is a true behavior of tigecycline. Further investigations are necessary to elucidate the mechanism.
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Determination of Atypical Nonlinear Plasma–Protein-Binding Behavior of Tigecycline Using an In Vitro Microdialysis Technique
Journal of pharmaceutical sciences, 2014Co-Authors: Jatinder Kaur Mukker, Ravishankar Prasad Singh, Hartmut DerendorfAbstract:ABSTRACT Tigecycline, a novel glycylcycline antibiotic, shows atypical nonlinear Plasma–Protein-Binding behavior using ultrafiltration and ultracentrifugation techniques. The mechanism of such counterintuitive behavior is currently unknown. Ultrafiltration and ultracentrifugation cause fractional change in Protein concentration and therefore may influence Plasma–Protein Binding. Microdialysis (MD), a novel technique, can sample unbound drugs without any change in fractional Protein concentration. To determine whether the atypical nonlinear Plasma–Protein-Binding behavior is not related to measurement technique, the Plasma–Protein Binding of tigecycline was determined using MD. A sensitive liquid chromatography-mass spectrometry method was developed and validated for the bioanalysis of tigecycline in the dialysate. The probe recoveries and Plasma–Protein Binding of tigecycline at four different concentration levels 0.1, 1, 10, and 100 μg/mL were determined. Similar to ultracentrifugation and ultrafiltration, MD also showed atypical nonlinear Plasma–Protein-Binding behavior of tigecycline up to 10 μg/mL, but unbound fraction increased at 100 μg/mL indicating saturation of mechanism responsible for atypical nonlinear behavior. This study concludes that the atypical nonlinear Binding behavior of tigecycline is not technique-dependent, rather it is a true behavior of tigecycline. Further investigations are necessary to elucidate the mechanism.
Jatinder Kaur Mukker - One of the best experts on this subject based on the ideXlab platform.
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determination of atypical nonlinear Plasma Protein Binding behavior of tigecycline using an in vitro microdialysis technique
Journal of Pharmaceutical Sciences, 2014Co-Authors: Jatinder Kaur Mukker, Ravishankar Prasad Singh, Hartmut DerendorfAbstract:ABSTRACT Tigecycline, a novel glycylcycline antibiotic, shows atypical nonlinear Plasma–Protein-Binding behavior using ultrafiltration and ultracentrifugation techniques. The mechanism of such counterintuitive behavior is currently unknown. Ultrafiltration and ultracentrifugation cause fractional change in Protein concentration and therefore may influence Plasma–Protein Binding. Microdialysis (MD), a novel technique, can sample unbound drugs without any change in fractional Protein concentration. To determine whether the atypical nonlinear Plasma–Protein-Binding behavior is not related to measurement technique, the Plasma–Protein Binding of tigecycline was determined using MD. A sensitive liquid chromatography-mass spectrometry method was developed and validated for the bioanalysis of tigecycline in the dialysate. The probe recoveries and Plasma–Protein Binding of tigecycline at four different concentration levels 0.1, 1, 10, and 100 μg/mL were determined. Similar to ultracentrifugation and ultrafiltration, MD also showed atypical nonlinear Plasma–Protein-Binding behavior of tigecycline up to 10 μg/mL, but unbound fraction increased at 100 μg/mL indicating saturation of mechanism responsible for atypical nonlinear behavior. This study concludes that the atypical nonlinear Binding behavior of tigecycline is not technique-dependent, rather it is a true behavior of tigecycline. Further investigations are necessary to elucidate the mechanism.
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Determination of Atypical Nonlinear Plasma–Protein-Binding Behavior of Tigecycline Using an In Vitro Microdialysis Technique
Journal of pharmaceutical sciences, 2014Co-Authors: Jatinder Kaur Mukker, Ravishankar Prasad Singh, Hartmut DerendorfAbstract:ABSTRACT Tigecycline, a novel glycylcycline antibiotic, shows atypical nonlinear Plasma–Protein-Binding behavior using ultrafiltration and ultracentrifugation techniques. The mechanism of such counterintuitive behavior is currently unknown. Ultrafiltration and ultracentrifugation cause fractional change in Protein concentration and therefore may influence Plasma–Protein Binding. Microdialysis (MD), a novel technique, can sample unbound drugs without any change in fractional Protein concentration. To determine whether the atypical nonlinear Plasma–Protein-Binding behavior is not related to measurement technique, the Plasma–Protein Binding of tigecycline was determined using MD. A sensitive liquid chromatography-mass spectrometry method was developed and validated for the bioanalysis of tigecycline in the dialysate. The probe recoveries and Plasma–Protein Binding of tigecycline at four different concentration levels 0.1, 1, 10, and 100 μg/mL were determined. Similar to ultracentrifugation and ultrafiltration, MD also showed atypical nonlinear Plasma–Protein-Binding behavior of tigecycline up to 10 μg/mL, but unbound fraction increased at 100 μg/mL indicating saturation of mechanism responsible for atypical nonlinear behavior. This study concludes that the atypical nonlinear Binding behavior of tigecycline is not technique-dependent, rather it is a true behavior of tigecycline. Further investigations are necessary to elucidate the mechanism.
Ravishankar Prasad Singh - One of the best experts on this subject based on the ideXlab platform.
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determination of atypical nonlinear Plasma Protein Binding behavior of tigecycline using an in vitro microdialysis technique
Journal of Pharmaceutical Sciences, 2014Co-Authors: Jatinder Kaur Mukker, Ravishankar Prasad Singh, Hartmut DerendorfAbstract:ABSTRACT Tigecycline, a novel glycylcycline antibiotic, shows atypical nonlinear Plasma–Protein-Binding behavior using ultrafiltration and ultracentrifugation techniques. The mechanism of such counterintuitive behavior is currently unknown. Ultrafiltration and ultracentrifugation cause fractional change in Protein concentration and therefore may influence Plasma–Protein Binding. Microdialysis (MD), a novel technique, can sample unbound drugs without any change in fractional Protein concentration. To determine whether the atypical nonlinear Plasma–Protein-Binding behavior is not related to measurement technique, the Plasma–Protein Binding of tigecycline was determined using MD. A sensitive liquid chromatography-mass spectrometry method was developed and validated for the bioanalysis of tigecycline in the dialysate. The probe recoveries and Plasma–Protein Binding of tigecycline at four different concentration levels 0.1, 1, 10, and 100 μg/mL were determined. Similar to ultracentrifugation and ultrafiltration, MD also showed atypical nonlinear Plasma–Protein-Binding behavior of tigecycline up to 10 μg/mL, but unbound fraction increased at 100 μg/mL indicating saturation of mechanism responsible for atypical nonlinear behavior. This study concludes that the atypical nonlinear Binding behavior of tigecycline is not technique-dependent, rather it is a true behavior of tigecycline. Further investigations are necessary to elucidate the mechanism.
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Determination of Atypical Nonlinear Plasma–Protein-Binding Behavior of Tigecycline Using an In Vitro Microdialysis Technique
Journal of pharmaceutical sciences, 2014Co-Authors: Jatinder Kaur Mukker, Ravishankar Prasad Singh, Hartmut DerendorfAbstract:ABSTRACT Tigecycline, a novel glycylcycline antibiotic, shows atypical nonlinear Plasma–Protein-Binding behavior using ultrafiltration and ultracentrifugation techniques. The mechanism of such counterintuitive behavior is currently unknown. Ultrafiltration and ultracentrifugation cause fractional change in Protein concentration and therefore may influence Plasma–Protein Binding. Microdialysis (MD), a novel technique, can sample unbound drugs without any change in fractional Protein concentration. To determine whether the atypical nonlinear Plasma–Protein-Binding behavior is not related to measurement technique, the Plasma–Protein Binding of tigecycline was determined using MD. A sensitive liquid chromatography-mass spectrometry method was developed and validated for the bioanalysis of tigecycline in the dialysate. The probe recoveries and Plasma–Protein Binding of tigecycline at four different concentration levels 0.1, 1, 10, and 100 μg/mL were determined. Similar to ultracentrifugation and ultrafiltration, MD also showed atypical nonlinear Plasma–Protein-Binding behavior of tigecycline up to 10 μg/mL, but unbound fraction increased at 100 μg/mL indicating saturation of mechanism responsible for atypical nonlinear behavior. This study concludes that the atypical nonlinear Binding behavior of tigecycline is not technique-dependent, rather it is a true behavior of tigecycline. Further investigations are necessary to elucidate the mechanism.
Kenneth R Korzekwa - One of the best experts on this subject based on the ideXlab platform.
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impact of ph on Plasma Protein Binding in equilibrium dialysis
Molecular Pharmaceutics, 2008Co-Authors: Christopher J Kochansky, Daniel R Mcmasters, Kenneth A Koeplinger, Haley H Kerr, Magang Shou, Kenneth R KorzekwaAbstract:Many pharmacokinetic analyses require unbound Plasma concentrations, including prediction of clearance, volume of distribution, drug-drug interactions, brain uptake analysis, etc. It is most often more convenient to measure the total drug concentration in Plasma rather than the unbound drug concentration. To arrive at unbound Plasma concentrations, separate in vitro determinations of the Plasma Protein Binding of a drug are usually carried out in serum or in Plasma, and the Plasma pharmacokinetic results are then mathematically adjusted by this fraction unbound ( f u,p). Plasma Protein Binding or the drug fraction unbound in Plasma ( f u,p) is known to be affected by Protein, drug, free fatty acid concentrations, lipoProtein partitioning, temperature, pH, and the presence or absence of other drugs/displacing agents within Plasma samples. Errors in f u,p determination caused by lack of adequate pH control in newer assay formats for Plasma Protein Binding (e.g., 96-well equilibrium thin walled polypropylene dialysis plates) will have significant drug-specific impact on these pharmacokinetic calculations. Using a diverse set of 55 drugs and a 96-well equilibrium dialysis plate format, the effect of variable pH during equilibrium dialysis experiments on measured values of f u,p was examined. Equilibrium dialysis of human Plasma against Dulbecco's phosphate buffered saline at 37 degrees C under an air or 10% CO 2 atmosphere for 22 h resulted in a final pH of approximately 8.7 and 7.4, respectively. The ratio of f u,p at pH 7.4 (10% CO 2) vs pH 8.7 (air) was >or=2.0 for 40% of the 55 compounds tested. Only one of the 55 compounds tested had a ratio <0.9. Select compounds were further examined in rat and dog Plasma. In addition, physicochemical properties were calculated for all compounds using ACD/Labs software or Merck in-house software and compared to Plasma Protein Binding results. Changes in Plasma Protein Binding due to pH increases which occurred during the equilibrium dialysis experiment were not species specific but were drug-specific, though nonpolar, cationic compounds had a higher likely hood of displaying pH-dependent Binding. These studies underscore the importance of effectively controlling pH in Plasma Protein Binding studies.
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Impact of pH on Plasma Protein Binding in equilibrium dialysis.
Molecular pharmaceutics, 2008Co-Authors: Christopher J Kochansky, Daniel R Mcmasters, Kenneth A Koeplinger, Haley H Kerr, Magang Shou, Kenneth R KorzekwaAbstract:Many pharmacokinetic analyses require unbound Plasma concentrations, including prediction of clearance, volume of distribution, drug-drug interactions, brain uptake analysis, etc. It is most often more convenient to measure the total drug concentration in Plasma rather than the unbound drug concentration. To arrive at unbound Plasma concentrations, separate in vitro determinations of the Plasma Protein Binding of a drug are usually carried out in serum or in Plasma, and the Plasma pharmacokinetic results are then mathematically adjusted by this fraction unbound ( f u,p). Plasma Protein Binding or the drug fraction unbound in Plasma ( f u,p) is known to be affected by Protein, drug, free fatty acid concentrations, lipoProtein partitioning, temperature, pH, and the presence or absence of other drugs/displacing agents within Plasma samples. Errors in f u,p determination caused by lack of adequate pH control in newer assay formats for Plasma Protein Binding (e.g., 96-well equilibrium thin walled polypropylene dialysis plates) will have significant drug-specific impact on these pharmacokinetic calculations. Using a diverse set of 55 drugs and a 96-well equilibrium dialysis plate format, the effect of variable pH during equilibrium dialysis experiments on measured values of f u,p was examined. Equilibrium dialysis of human Plasma against Dulbecco's phosphate buffered saline at 37 degrees C under an air or 10% CO 2 atmosphere for 22 h resulted in a final pH of approximately 8.7 and 7.4, respectively. The ratio of f u,p at pH 7.4 (10% CO 2) vs pH 8.7 (air) was >or=2.0 for 40% of the 55 compounds tested. Only one of the 55 compounds tested had a ratio
Tony Velkov - One of the best experts on this subject based on the ideXlab platform.
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the Plasma Protein Binding proteome of ertapenem a novel compound centric proteomic approach for elucidating drug Plasma Protein Binding interactions
ACS Chemical Biology, 2016Co-Authors: Mark Baker, Elena K Schneider, Johnny X Huang, Mark E Cooper, Tony VelkovAbstract:Ertapenem is an important first-line carbapenem antibiotic used for the treatment of aerobic Gram-negative bacterial infections. It is the only marketed carbapenem that is highly bound to Plasma Proteins and displays a concentration-dependent and saturable Plasma Protein Binding profile. To date, the Plasma components responsible for sequestering ertapenems antibacterial activity remain uncharacterized. In the present study, we have employed an orthogonal, multiplatform approach, including novel compound-centric displacement proteomics and surface plasmon resonance to characterize the Plasma Protein Binding proteome of ertapenem. In proof-of-concept, the capacity of physiological cocktails of the identified Plasma Proteins to inhibit the antibacterial activity of ertapenem was assessed with in vitro microbiological assays. We show that fibrinogen, complement C4, haptoglobulin, α-1-antitrypsin, fibronectin, transferrin, immunoglobulin G, hemopexin, and humans serum albumin are responsible for the majority ...