Determination of Atypical Nonlinear Plasma–Protein-Binding Behavior of Tigecycline Using an In Vitro Microdialysis Technique |
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| Institution: | 1. Faculty of Pharmacy, University of Montreal, 2940 Chemin de la Polytechnique, Montreal, Quebec H3T 1J4, Canada;2. CRCHUM, Centre de Recherche du Centre Hospitalier de l’Université de Montréal, 900 Saint Denis Street, Montreal, Quebec H2X 0A9, Canada;1. Division of CBRN Defence, Institute of Nuclear Medicine and Allied Sciences (INMAS), New Delhi 110054, India;2. Department of Biotechnology, Jamia Hamdard, New Delhi 110062, India;3. Office of DG (LS), Defence Research and Development Organisation, DRDO Bhawan, New Delhi, India;1. School of Chemical Engineering and Technology, Tianjin University, Tianjin 300072, China;2. Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL 32610, USA;3. Department of Molecular Genetics and Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA;4. Key Laboratory of Drug Delivery Technology and Pharmacokinetics, Tianjin Institute of Pharmaceutical Research, Tianjin 300193, China;1. Division of Biopharmaceutics and Pharmacokinetics, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha 410013, China;2. Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China;3. Institute of Clinical Pharmacy, The Second Xiangya Hospital, Central South University, Changsha 410011, China;1. State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing 400716, PR China;2. Division of Scientific Research and Training, General Hospital of PLA Chengdu Military Area Command, Chengdu, Sichuan 610083, PR China;3. Institute of Urinary Surgery, Southwest Hospital, Third Military Medical University, Chongqing 400038, PR China |
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| 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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