Dose dependent pharmacokinetics of mezlocillin in subjects with normal and impaired renal function

The effects of dose and renal function on the pharmacokinetics of mezlocillin were assessed in six normal volunteers and in ten chronic renal disease outpatients. Comparison was made to data from six functionally anephric patients given a dose during haemodialysis (HD). Each non dialysed subject received a 1 and 5 dose in a randomized cross over manner. At both dosage levels serum concentrations declined biexponentially as a function of time. Dose and time average pharmacokinetic parameters revealed marked dose dependence. Plasma clearance (Clp) and both renal (Clr) and nonrenal clearance (Clnr) were significantly decreased at the higher dose, with Clnr exhibiting more marked dose-dependence than Clr. Both central KJ and steady state (Kss) volumes of distribution were smaller at the higher dose. Volumes of distribution at the 1 g dose were similar to those of HD patients. Saturability of tissue uptake, of Clr or of biliary clearance could partially explain the dose dependent disposition. Clp and Clr correlated linearly with creatinine clearance (Clcr) at both dosage levels, but the 5 g 1 g clearance ratios did not correlate with Cl Clnr at the 5 g dose was relatively unaffected (2-71/h/l-73 m2) by varying Clcr. However, at the 1 g dose, Cl, decreased with decreasing C extrapolation of the regression line to a C1CT of zero yielded a Clw approximately equal to that measured for HD patients. Dosing recommendations for mezlocillin should take into account the concomitant effects of dose and renal function on its pharmacokinetics.