Jungbluth G L, Jusko W J
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo 14260.
Antimicrob Agents Chemother. 1989 Jun;33(6):839-43. doi: 10.1128/AAC.33.6.839.
The pharmacokinetics of mezlocillin were examined in rats following bolus intravenous doses of 20 or 200 mg/kg. Mezlocillin exhibited bi- or triexponential disposition profiles, and the area under the concentration-time curve increased nonproportionally with dose similar to reported findings in humans. Apparent total, renal, and nonrenal clearances and the volume of distribution at steady-state all decreased by 45 to 50% with the higher dose, and the elimination half-life was longer (8 +/- 2 versus 15 +/- 3 min). Mezlocillin exhibits low saturable binding in rat serum, ranging from 20 to 40% bound. Pharmacokinetic parameters based on free drug demonstrated dose-dependent characteristics similar to those with total drug. Use of the volume of distribution from the low dose allowed calculation of the true mean residence time. The linear relationship between dose and mean residence time from free concentrations yielded pooled Michaelis-Menten parameters. These were used as initial estimates in the simultaneous nonlinear fitting of the low- and high-dose mean free concentrations to a three-compartment model with sequential distribution and Michaelis-Menten elimination to describe the nonlinearity of mezlocillin disposition further.
在大鼠静脉注射大剂量20或200mg/kg的美洛西林后，对其药代动力学进行了研究。美洛西林呈现出双指数或三指数处置曲线，浓度-时间曲线下面积随剂量增加而非比例增加，这与在人类中的报道结果相似。较高剂量时，表观总清除率、肾清除率和非肾清除率以及稳态分布容积均降低45%至50%，消除半衰期延长（8±2分钟对15±3分钟）。美洛西林在大鼠血清中的饱和结合率较低，结合率在20%至40%之间。基于游离药物的药代动力学参数显示出与总药物相似的剂量依赖性特征。使用低剂量的分布容积可计算出真正的平均驻留时间。剂量与游离浓度的平均驻留时间之间的线性关系产生了汇总的米氏参数。这些参数被用作初始估计值，用于将低剂量和高剂量的平均游离浓度同时非线性拟合到具有顺序分布和米氏消除的三室模型中，以进一步描述美洛西林处置的非线性。
