The aim of this study was to investigate the factors limiting the blood-brain barrier (BBB) transport of
colistin in healthy mice and to assess the impact of systemic
inflammation on the transport of this
antibiotic across the BBB.
Colistin sulfate (40 mg/kg) was administered subcutaneously to Swiss outbred mice as single and multiple doses to determine any relationship between brain uptake and plasma concentrations of
colistin. To assess the effect of
P-glycoprotein (P-gp) on BBB transport,
colistin sulfate (5 mg/kg) was concomitantly administered intravenously with
PSC833 or
GF120918 (10 mg/kg). Systemic
inflammation was induced by three
intraperitoneal injections of
lipopolysaccharide (LPS; 3 mg/kg), and BBB transport of
colistin was subsequently measured following subcutaneous administration and by an in situ brain perfusion. The brain uptake of
colistin was low following single and multiple subcutaneous doses, with brain-to-plasma concentration ratios ranging between 0.021 and 0.037, and this was not significantly enhanced by coadministration of
GF120918 or
PSC833 (P > 0.05). LPS significantly increased the brain uptake of subcutaneously administered
colistin with area under the brain concentration time curve (AUC(brain)) values of 11.7 ± 2.7 μg·h/g and 4.0 ± 0.3 μg·h/g for LPS- and saline-treated mice, respectively (mean ± standard deviation). Similarly, in situ perfusion of
colistin led to higher
antibiotic brain concentrations in LPS-treated animals than in saline-treated animals, with
colistin brain-to-perfusate concentration ratios of 0.019 ± 0.001 and 0.014 ± 0.001, respectively. This study demonstrates that the BBB transport of
colistin is negligible in healthy mice; however, brain concentrations of
colistin can be significantly enhanced during systemic
inflammation, as might be observed in infected patients.