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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Impact of p-glycoprotein inhibition and lipopolysaccharide administration on blood-brain barrier transport of colistin in mice.
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Impact of p-glycoprotein inhibition and lipopolysaccharide administration on blood-brain barrier transport of colistin in mice.

机译：对p-糖蛋白抑制和脂多糖给药对粘菌素在小鼠中的血脑屏障运输的影响。

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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 mug.h/g and 4.0 +/- 0.3 mug.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.
机译：这项研究的目的是调查限制健康小鼠中粘菌素的血脑屏障（BBB）转运的因素，并评估全身性炎症对这种抗生素跨BBB转运的影响。以单剂量和多剂量皮下给予瑞士远亲小鼠皮下给予硫酸共利斯汀（40 mg / kg），以确定脑摄取与粘菌素血浆浓度之间的任何关系。为了评估P-糖蛋白（P-gp）对BBB转运的影响，将硫酸粘杆菌素（5 mg / kg）与PSC833或GF120918（10 mg / kg）静脉内同时给药。通过腹膜内注射脂多糖（LPS; 3 mg / kg）3次诱发全身性炎症，随后在皮下给药和原位脑灌注后测量粘菌素的BBB转运。单次和多次皮下给药后大肠粘液素的脑吸收率很低，脑与血浆的浓度比在0.021至0.037之间，并且通过并用GF120918或PSC833并不能显着提高这种吸收（P> 0.05）。 LPS显着提高了皮下注射粘菌素的大脑摄取，其LPS-的脑部浓度时间曲线（AUC（大脑））值分别为11.7 +/- 2.7 mug.h / g和4.0 +/- 0.3 mug.h / g。分别用生理盐水和生理盐水处理的小鼠（平均值+/-标准偏差）。类似地，粘多糖素的原位灌注在LPS处理的动物中比在盐水处理的动物中导致更高的抗生素脑浓度，粘菌素的脑与灌注液的浓度比分别为0.019 +/- 0.001和0.014 +/- 0.001。这项研究表明，在健康小鼠中大肠菌素的血脑屏障运输是微不足道的。然而，在全身性炎症过程中，大肠粘菌素的脑浓度可以显着提高，就像在感染患者中观察到的那样。

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