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  • Title: Dose-dependent pharmacokinetics of mezlocillin in rats.
    Author: Jungbluth GL, Jusko WJ.
    Journal: Antimicrob Agents Chemother; 1989 Jun; 33(6):839-43. PubMed ID: 2764534.
    Abstract:
    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.
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