Role of Divalent Metal Ions in Atypical Nonlinear Plasma Protein Binding Behavior of Tigecycline.
J Pharm Sci
; 105(11): 3409-3414, 2016 11.
Article
em En
| MEDLINE
| ID: mdl-27616672
ABSTRACT
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.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cloreto de Cálcio
/
Proteínas Sanguíneas
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Cloreto de Magnésio
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Dinâmica não Linear
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Minociclina
Limite:
Humans
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article