Dose-dependent pharmacokinetics of mezlocillin in relation to renal impairment.

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RESUMO

The dose dependence of mezlocillin pharmacokinetics was examined in relation to renal function after intravenous doses of 1 and 5 g in 16 subjects with various degrees of renal impairment. Dose and time-average model-independent physiological parameters were calculated from plasma concentration and urinary excretion data. Lack of superimposition of plasma concentration profiles occurred between dosage levels with a twofold exaggeration of areas under the curve produced between doses of 1 and 5 g. Decreased plasma clearances at the higher dose were caused partly by nonlinear renal clearance, but more markedly by dose dependence in nonrenal clearances. At each dosage level, these parameters were examined in relation to creatinine clearances. Plasma and renal clearances exhibited a typical linear correlation with creatinine clearance for each dose level. However, nonrenal clearances demonstrated a linear relationship with creatinine clearance at the 1-g dose, but apparent saturation of this pathway produced lower and relatively constant nonrenal clearance values at the 5-g dose. Mezlocillin pharmacokinetics are thus influenced by both dose and renal function over the dosage range of 1 to 5 g. Saturation in renal clearance and probably in biliary clearance explains the unusual disposition characteristics of mezlocillin observed in this and previously reported studies.

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