Penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs).
OBJECTIVE
To evaluate the penetration, efflux and intracellular activity of tigecycline in human polymorphonuclear neutrophils (PMNs).


METHODS
PMNs were isolated from fresh whole blood and tested for viability and purity prior to use. Tigecycline drug uptake was evaluated by incubating 5 x 10(6) cells/mL at 37 degrees C up to 3 h at tigecycline concentrations of 1, 2, 5 and 10 mg/L. Drug efflux from PMNs was determined following a 2 h incubation with tigecycline at 10 mg/L. Its intracellular activity against Staphylococcus aureus was evaluated following tigecycline extracellular exposures of 1 mg/L.


RESULTS
Tigecycline uptake was rapid and achieved high concentrations within PMNs with maximal penetration noted at 1 h of incubation. At 1 h, dose-dependent intracellular concentrations ranged from 15.83 +/- 11.09 mg/L to 264 +/- 54.60 mg/L at tigecycline 1 and 10 mg/L, respectively. At these exposures, intracellular drug concentrations were approximately 20 and 30 times higher at 1 h than extracellular concentrations. By 3 h, tigecycline displayed sustained high intracellular exposures. Tigecycline cell efflux followed first order kinetics with a half-life of 1.39 h. Tigecycline was bacteriostatic against intracellular S. aureus.


CONCLUSIONS
Tigecycline rapidly achieved high intracellular concentrations in PMNs and exhibited static activity against S. aureus supporting its potential clinical utilization.
Ong
Christine T
CT
Center for Anti-Infective Research and Development, Hartford Hospital, 80 Seymour Street, Hartford, CT 06102, USA.
Babalola
Chinedum P
CP
Nightingale
Charles H
CH
Nicolau
David P
DP
D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008826:Microbial Sensitivity Tests; D008911:Minocycline / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism* / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000472:pathogenicity; D000078304:Tigecycline
D000900:Anti-Bacterial Agents; D000078304:Tigecycline; D008911:Minocycline