OBJECTIVES To measure the effect of probenecid, fasting and fed, on flucloxacillin pharmacokinetic and pharmacodynamic endpoints. METHODS Flucloxacillin 1000 mg orally was given to 11 volunteers alone while fasting ('flucloxacillin alone'), and with probenecid 500 mg orally while fasting ('probenecid fasting') and with food ('probenecid fed'). Flucloxacillin pharmacokinetic and pharmacodynamic endpoints were compared. RESULTS Probenecid, fasting and fed, increased free plasma flucloxacillin area under the concentration-time curve (zero to infinity) ∼1.65-fold (p < 0.01) versus flucloxacillin alone. Probenecid fed prolonged time to peak flucloxacillin concentrations ∼2-fold versus the other two regimens (p < 0.01). Probenecid fasting or fed increased free flucloxacillin concentrations exceeding 30%, 50% and 70% of the first 6, 8 and 12 h post-dose by 1.58- to 5.48-fold compared with flucloxacillin alone. As an example of this pharmacodynamic improvement, the probability of target attainment of free concentrations above the minimum inhibitory concentration for Staphylococcus aureus (0.5 mg/L) for 50% of a 6-hour dose interval was > 80% for flucloxacillin plus probenecid (fasting or fed) and < 20% for flucloxacillin alone. CONCLUSIONS Probenecid increased flucloxacillin exposure, with predicted pharmacodynamic effects greater than pharmacokinetic effects because of the altered shape of the concentration-time curve. Probenecid may improve the applicability of oral flucloxacillin regimens.

中文翻译：

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丙磺舒和食物对健康志愿者中氟氯西林药代动力学和药效学的影响。

目的测定丙磺舒，禁食和进食对氟氯西林药代动力学和药效学终点的影响。方法禁食时单独给11名志愿者口服1000mg氟氯西林（“单独氟氯西林”），禁食时口服丙磺舒500mg（禁食）和食物（禁食）。比较了氟氯西林的药代动力学和药效学终点。结果与单独使用氟氯西林相比，在浓度-时间曲线（零到无穷大）下，丙磺舒，禁食和进食的游离血浆氟氯西林面积增加了1.65倍（p <0.01）。与其他两种方案相比，丙磺舒喂食氟氯西林峰值浓度的时间延长了约2倍（p <0.01）。空腹或进食丙磺舒会增加氟氯西林的游离浓度超过30％，与单独使用氟氯西林相比，给药后头6、8和12 h分别有50％和70％的1.58至5.48倍。作为这种药效学改进的一个例子，在6小时剂量间隔的50％内，达到目标浓度的自由浓度高于金黄色葡萄球菌最低抑制浓度（0.5 mg / L）的可能性大于氟氯西林加丙磺舒的80％（禁食）或进食），单独使用氟氯西林的<20％。结论丙磺舒增加氟氯西林的暴露，由于浓度-时间曲线形状的改变，预测的药效学作用大于药代动力学作用。丙磺舒可改善口服氟氯西林方案的适用性。对于氟氯西林加丙磺舒（禁食或进食），在6小时剂量间隔的50％内达到金黄色葡萄球菌最低抑菌浓度（0.5 mg / L）的游离浓度高于最低抑制浓度的概率为> 80％，而对于空腹或禁食为<20％单独使用氟氯西林。结论丙磺舒增加氟氯西林的暴露，由于浓度-时间曲线形状的改变，预测的药效学作用大于药代动力学作用。丙磺舒可改善口服氟氯西林方案的适用性。对于氟氯西林加丙磺舒（禁食或进食），在6小时剂量间隔的50％内达到金黄色葡萄球菌最低抑菌浓度（0.5 mg / L）的游离浓度高于最低抑制浓度的概率为> 80％，而对于空腹或禁食为<20％单独使用氟氯西林。结论丙磺舒增加氟氯西林的暴露，由于浓度-时间曲线形状的改变，预测的药效学作用大于药代动力学作用。丙磺舒可改善口服氟氯西林方案的适用性。结论丙磺舒增加氟氯西林的暴露，由于浓度-时间曲线形状的改变，预测的药效学作用大于药代动力学作用。丙磺舒可改善口服氟氯西林方案的适用性。结论丙磺舒增加氟氯西林的暴露，由于浓度-时间曲线形状的改变，预测的药效学作用大于药代动力学作用。丙磺舒可改善口服氟氯西林方案的适用性。