Role of Divalent Metal Ions in Atypical Nonlinear Plasma Protein Binding Behavior of Tigecycline.
In typical nonlinear plasma protein binding (PPB) behavior, the free fraction increases with increasing total concentrations. In contrast, when a drug exhibits atypical nonlinear PPB behavior, the free fraction decreases with increasing total concentrations. Tigecycline, a novel glycylcycline, exhibits atypical nonlinear PPB behavior, but the mechanism of such behavior is currently unknown. Because tigecycline can form complexes with metal ions, an interaction between metal ion, tigecycline, and plasma proteins was hypothesized but not further investigated. The current work explores the role of metal ions in the atypical nonlinear PPB behavior of tigecycline and proposes a plausible mechanism of atypical nonlinear PPB behavior. The addition of ethylenediaminetetraacetic acid resulted in 10- to 30-fold higher unbound fractions, and the atypical behavior was nullified. The saturation of ethylenediaminetetraacetic acid chelation, by addition of excessive divalent metal ions, such as calcium and magnesium, led to the return of the atypical nonlinear PPB behavior. Different possible mechanisms were evaluated by simulation, and a plausible mechanism was proposed.
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Ravi Shankar Prasad
RSP
Singh
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Jatinder Kaur
JK
Mukker
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Amelia N
AN
Deitchman
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610.
Stephanie K
SK
Drescher
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, Florida 32610. Electronic address: hartmut@cop.ufl.edu.
Hartmut
H
Derendorf
D000900:Anti-Bacterial Agents / Q000378:metabolism; D001798:Blood Proteins / Q000378:metabolism*; D002122:Calcium Chloride / Q000378:metabolism*; D002413:Cations, Divalent / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007477:Ions; D015636:Magnesium Chloride / Q000378:metabolism*; D008911:Minocycline / Q000031:analogs & derivatives* / Q000378:metabolism; D017711:Nonlinear Dynamics; D011485:Protein Binding / Q000502:physiology; D000078304:Tigecycline
D000900:Anti-Bacterial Agents; D001798:Blood Proteins; D002413:Cations, Divalent; D007477:Ions; D015636:Magnesium Chloride; D000078304:Tigecycline; D008911:Minocycline; D002122:Calcium Chloride
atypical nonlinear plasma protein binding; mechanism; metal-ion complexation; nonlinear plasma protein binding; tigecycline